G2Cdb::Gene report

Gene id
G00002141
Gene symbol
SEPT5 (HGNC)
Species
Homo sapiens
Description
septin 5
Orthologue
G00000892 (Mus musculus)

Databases (8)

Curated Gene
OTTHUMG00000030187 (Vega human gene)
Gene
ENSG00000184702 (Ensembl human gene)
5413 (Entrez Gene)
552 (G2Cdb plasticity & disease)
SEPT5 (GeneCards)
Literature
602724 (OMIM)
Marker Symbol
HGNC:9164 (HGNC)
Protein Sequence
Q99719 (UniProt)

Synonyms (2)

  • H5
  • HCDCREL-1

Literature (29)

Pubmed - other

  • Parkin regulates Eg5 expression by Hsp70 ubiquitination-dependent inactivation of c-Jun NH2-terminal kinase.

    Liu M, Aneja R, Sun X, Xie S, Wang H, Wu X, Dong JT, Li M, Joshi HC and Zhou J

    Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.

    Eg5 is a motor protein of the kinesin family that is critical for spindle assembly during mitosis and has recently been implicated in tumorigenesis. It is largely unknown how Eg5 expression is regulated in cells. In this study, we present the first evidence that the cellular Eg5 level is down-regulated by Parkin, an E3 ubiquitin ligase well known for its role in the development of Parkinson disease. Our data show that Parkin does not trigger Eg5 protein degradation through the ubiquitin-proteasome pathway. Instead, Parkin represses Eg5 gene transcription by blocking c-Jun binding to the activator protein 1 site present in the Eg5 promoter. Our data further show that Parkin inactivates c-Jun NH2-terminal kinase (JNK), resulting in decreased phosphorylation of c-Jun. The inactivation of JNK is further mediated by multiple monoubiquitination of Hsp70. Importantly, both the ubiquitination of Hsp70 and the subsequent inactivation of the JNK-c-Jun pathway are crucial for Parkin to down-regulate Eg5 expression. These results thus uncover a novel function for Parkin in modulating the expression of Eg5 through the Hsp70-JNK-c-Jun signaling pathway.

    The Journal of biological chemistry 2008;283;51;35783-8

  • HSP70 and constitutively active HSF1 mediate protection against CDCrel-1-mediated toxicity.

    Jung AE, Fitzsimons HL, Bland RJ, During MJ and Young D

    Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.

    Defects in cellular quality control mechanisms are thought to contribute to the neuropathology of Parkinson's disease (PD). Overexpressing heat shock proteins (HSPs) may constitute a powerful therapeutic strategy for PD, because they boost the ability of the cell to eliminate unwanted proteins. We investigated the neuroprotective potential of HSP70, HSP40, and H-BH, a constitutively active form of heat shock factor 1, in a rat model of PD based on adeno-associated virus (AAV) vector-mediated overexpression of CDCrel-1, a parkin substrate known to be toxic to dopaminergic neurons. AAV vector-mediated overexpression of H-BH and of HSP70 afforded similar levels of protection against CDCrel-1 toxicity, with approximately 20% improvement in survival of dopaminergic neurons as compared to the controls. The assessment of protection conferred was made using tyrosine hydroxylase (TH) and HuC/D immunohistochemistry and Fluoro-Gold retrograde tracing, and by observing the extent of preservation of spontaneous function and also the extent of drug-induced motor function. In contrast to H-BH and HSP70, HSP40 overexpression exacerbated CDCrel-1-mediated cell death. Real-time reverse transcriptase (RT)-PCR analysis showed that H-BH had the effect of upregulating endogenous HSP70 and HSP40 mRNA levels 10-fold and 4-fold over basal levels, respectively, whereas AAV vector-mediated HSP70 and HSP40 mRNA levels were over 100-fold higher. Our results suggest that a comparatively modest upregulation of multiple HSPs may be an effective approach for achieving significant neuroprotection in PD.

    Funded by: NINDS NIH HHS: NS44576, R01 NS044576, R01 NS044576-06

    Molecular therapy : the journal of the American Society of Gene Therapy 2008;16;6;1048-55

  • Septin expression in proliferative retinal membranes.

    Xin X, Pache M, Zieger B, Bartsch I, Prünte C, Flammer J and Meyer P

    Department of Ophthalmic Pathology, University of Basel, Basel, Switzerland.

    We undertook this study to evaluate the expression of septin family members SEPT5, SEPT8, and SEPT11 in proliferative retinal membranes. Epiretinal membranes (ERM) were obtained from seven patients with proliferative vitreoretinopathy (PVR) and from four patients and four postmortem eyes with proliferative diabetic retinopathy (PDR). Subretinal membranes (SRM) were obtained from one patient and six postmortem eyes. Membranes were examined by immunohistochemical staining of paraffin sections using polyclonal antibodies against SEPT5, SEPT8, and SEPT11 and an ABC detection system. SEPT8 expression was detected in all ERM and SRM, with an exceptionally strong expression of 100% for ERM of PVR, 63% for PDR membranes, and 57% for SRM. SEPT11 was identified in 91% of all cases, with strong expression of 14%, 25%, and 14% in ERM of PVR, PDR, and SRM, respectively. SEPT5 was seen in 54% of all cases; strong immunostaining was found in only one case of PVR membranes. Our finding suggests a role for members of the septin family in the development of proliferative retinal membranes.

    The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 2007;55;11;1089-94

  • Human endothelial cell septins: SEPT11 is an interaction partner of SEPT5.

    Bläser S, Röseler S, Rempp H, Bartsch I, Bauer H, Lieber M, Lessmann E, Weingarten L, Busse A, Huber M and Zieger B

    Department of Paediatrics and Adolescent Medicine, University Hospital Freiburg, Mathildenstrasse 1, D-79106 Germany.

    The septin SEPT11 is a novel member of the highly conserved septin family. Septins are cytoskeletal GTPases, which form heteropolymeric complexes. They are involved in cytokinesis and other cellular processes, such as vesicle trafficking and exocytosis. SEPT11 has strong homology to SEPT8. Previously, we identified the interaction of SEPT5 and SEPT8. Using the yeast two-hybrid system, we now demonstrate that SEPT11 partners with SEPT5. The molecular interaction of SEPT11 with SEPT5 was verified by coprecipitation of SEPT5 and SEPT11 from lysates of the human T-cell leukaemia cell line JURKAT and by fluorescence resonance energy transfer. The interaction between SEPT5 and SEPT11 requires the GTP-binding domain and the C-terminal extension. Western analysis in various mouse and human tissues revealed that expression of SEPT11 is restricted to the same tissues as those expressing SEPT5, suggesting that SEPT11 and SEPT5 are components of a cell-specific septin complex. SEPT5, which is expressed in human umbilical vein endothelial cells (HUVECs), has been reported to play an important role in exocytosis. We now report that HUVECs also express SEPT11. Given the interactivity between SEPT5 and SEPT11 as shown above and their coexpression in HUVECs, it may be that a complex formed by these two proteins is involved in the exocytosis mechanism in HUVECs.

    The Journal of pathology 2006;210;1;103-10

  • A human protein-protein interaction network: a resource for annotating the proteome.

    Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, Stroedicke M, Zenkner M, Schoenherr A, Koeppen S, Timm J, Mintzlaff S, Abraham C, Bock N, Kietzmann S, Goedde A, Toksöz E, Droege A, Krobitsch S, Korn B, Birchmeier W, Lehrach H and Wanker EE

    Max Delbrueck Center for Molecular Medicine, 13092 Berlin-Buch, Germany.

    Protein-protein interaction maps provide a valuable framework for a better understanding of the functional organization of the proteome. To detect interacting pairs of human proteins systematically, a protein matrix of 4456 baits and 5632 preys was screened by automated yeast two-hybrid (Y2H) interaction mating. We identified 3186 mostly novel interactions among 1705 proteins, resulting in a large, highly connected network. Independent pull-down and co-immunoprecipitation assays validated the overall quality of the Y2H interactions. Using topological and GO criteria, a scoring system was developed to define 911 high-confidence interactions among 401 proteins. Furthermore, the network was searched for interactions linking uncharacterized gene products and human disease proteins to regulatory cellular pathways. Two novel Axin-1 interactions were validated experimentally, characterizing ANP32A and CRMP1 as modulators of Wnt signaling. Systematic human protein interaction screens can lead to a more comprehensive understanding of protein function and cellular processes.

    Cell 2005;122;6;957-68

  • Peanut-like 1 (septin 5) gene expression in normal and neoplastic human endocrine pancreas.

    Capurso G, Crnogorac-Jurcevic T, Milione M, Panzuto F, Campanini N, Dowen SE, Di Florio A, Sette C, Bordi C, Lemoine NR and Delle Fave G

    Digestive and Liver Disease Unit, II Medical School, University La Sapienza, Roma, Italy.

    Peanut-like 1 (PNUTL1) is a septin gene which is expressed at high levels in human brain. There it plays a role in the process of membrane fusion during exocytosis by interacting with syntaxin and synaptophysin. As the secretory apparatus of pancreatic islet cells closely resembles that of neurons, we decided to study the expression of PNUTL1 in the human endocrine pancreas, both in normal islets and in pancreatic endocrine tumors (PETs). Normal pancreatic tissue, purified islets, 11 PETs and two cell lines were used to evaluate the presence of PNUTL1 by RT-PCR and Western blot. The expression of the PNUTL1 protein was also evaluated by immunohistochemistry on normal pancreas, additional 26 PETs, eight pancreatic adenocarcinomas, one mixed endocrine-exocrine pancreatic neoplasm, a specimen of solid papillary pseudomucinous tumor, an adult islet cell hyperplasia and a case of neonatal nesidioblastosis. In addition, a tissue array (LandMark High Density Cancer Tissue MicroArray) comprising 280 various tumor and matched normal specimens was utilized. In PETs, the expression of pancreatic hormones, chromogranin-A, synaptophysin and Ki-67 were also evaluated. In the normal pancreas PNUTL1 expression is almost exclusively confined to the islet cells, weak expression was occasionally seen in some acinar cells, while immunoreactivity was completely absent in the ductal epithelia. PNUTL1 expression is maintained at similar high levels in hyperplastic and neoplastic islet cells, but this did not correlate with any of the clinicopathological data nor with proliferation status in PETs. Weak immunoreactivity was also noted in a proportion of exocrine neoplasms. Our findings describe for the first time the high expression levels of PNUTL1 in human pancreatic endocrine cells that suggests a similar role of this protein in islet cells to that demonstrated in neuronal tissues, and warrants further functional studies of this protein.

    Neuroendocrinology 2005;81;5;311-21

  • Phosphoproteomic analysis of the developing mouse brain.

    Ballif BA, Villén J, Beausoleil SA, Schwartz D and Gygi SP

    Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.

    Proper development of the mammalian brain requires the precise integration of numerous temporally and spatially regulated stimuli. Many of these signals transduce their cues via the reversible phosphorylation of downstream effector molecules. Neuronal stimuli acting in concert have the potential of generating enormous arrays of regulatory phosphoproteins. Toward the global profiling of phosphoproteins in the developing brain, we report here the use of a mass spectrometry-based methodology permitting the first proteomic-scale phosphorylation site analysis of primary animal tissue, identifying over 500 protein phosphorylation sites in the developing mouse brain.

    Funded by: NHGRI NIH HHS: HG00041

    Molecular & cellular proteomics : MCP 2004;3;11;1093-101

  • The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

    Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Morrin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J and MGC Project Team

    The National Institutes of Health's Mammalian Gene Collection (MGC) project was designed to generate and sequence a publicly accessible cDNA resource containing a complete open reading frame (ORF) for every human and mouse gene. The project initially used a random strategy to select clones from a large number of cDNA libraries from diverse tissues. Candidate clones were chosen based on 5'-EST sequences, and then fully sequenced to high accuracy and analyzed by algorithms developed for this project. Currently, more than 11,000 human and 10,000 mouse genes are represented in MGC by at least one clone with a full ORF. The random selection approach is now reaching a saturation point, and a transition to protocols targeted at the missing transcripts is now required to complete the mouse and human collections. Comparison of the sequence of the MGC clones to reference genome sequences reveals that most cDNA clones are of very high sequence quality, although it is likely that some cDNAs may carry missense variants as a consequence of experimental artifact, such as PCR, cloning, or reverse transcriptase errors. Recently, a rat cDNA component was added to the project, and ongoing frog (Xenopus) and zebrafish (Danio) cDNA projects were expanded to take advantage of the high-throughput MGC pipeline.

    Funded by: PHS HHS: N01-C0-12400

    Genome research 2004;14;10B;2121-7

  • Human septin-septin interactions as a prerequisite for targeting septin complexes in the cytosol.

    Martínez C, Sanjuan MA, Dent JA, Karlsson L and Ware J

    The Roon Research Center for Arteriosclerosis and Thrombosis, Division of Experimental Hemostasis and Thrombosis, Department of Molecular and Experimental Medicine The Scripps Research Institute, La Jolla, CA 92037, USA.

    Septins are a cytosolic GTP-binding protein family first characterized in yeast, but gaining increasing recognition as critical protagonists in higher eukaryotic cellular events. Mammalian septins have been associated with cytokinesis and exocytosis, along with contributing to the development of neurological disorders. Ten different septins, divided into four groups, have been identified in mammals, and individual septins are capable of interacting with each other to form macromolecular complexes. The present study characterizes the structural requirements for human septin-septin interactions using a yeast two-hybrid system. We focus on three septins that are highly expressed in platelets and neurons, SEPT4 [previously designated H5, CDCrel-2 (cell-division-control-related-2), PNUTL2], SEPT5 (CDCrel-1, PNUTL1) and SEPT8 (KIAA0202). Each of these three septins contains a characteristic domain structure consisting of unique N- and C-termini, and a central core domain conserved among the family of proteins. The yeast two-hybrid system yielded data consistent with a model where each of the three septins can interact with itself (homotypic assembly) or with one of the other septins (heterotypic assembly). For SEPT5 and SEPT8, the results illustrate a model whereby heterotypic septin assembly is dependent on the conserved central core domain and homotypic interactions require the N- and C-termini of each protein. We also characterized a model in which the proper cellular localization of SEPT5 and SEPT8 requires concomitant expression of both proteins. Co-transfection of SEPT5 and SEPT8 results in both proteins targeted to a vesicular-like location. Therefore the cellular repertoire of human septins has an impact on function by targeting septin macromolecular complexes to specific cellular locations.

    Funded by: NHLBI NIH HHS: HL69951, R01 HL069951, R01 HL069951-04

    The Biochemical journal 2004;382;Pt 3;783-91

  • A protein interaction framework for human mRNA degradation.

    Lehner B and Sanderson CM

    MRC Rosalind Franklin Centre for Genomics Research, Hinxton, Cambridge CB10 1SB, United Kingdom.

    The degradation of mRNA is an important regulatory step in the control of gene expression. However, mammalian RNA decay pathways remain poorly characterized. To provide a framework for studying mammalian RNA decay, a two-hybrid protein interaction map was generated using 54 constructs from 38 human proteins predicted to function in mRNA decay. The results provide evidence for interactions between many different proteins required for mRNA decay. Of particular interest are interactions between the poly(A) ribonuclease and the exosome and between the Lsm complex, decapping factors, and 5'-->3' exonucleases. Moreover, multiple interactions connect 5'-->3' and 3'-->5' decay proteins to each other and to nonsense-mediated decay factors, providing the opportunity for coordination between decay pathways. The interaction network also predicts the internal organization of the exosome and Lsm complexes. Additional interactions connect mRNA decay factors to many novel proteins and to proteins required for other steps in gene expression. These results provide an experimental insight into the organization of proteins required for mRNA decay and their coupling to other cellular processes, and the physiological relevance of many of these interactions are supported by their evolutionary conservation. The interactions also provide a wealth of hypotheses to guide future research on mRNA degradation and demonstrate the power of exhaustive protein interaction mapping in aiding understanding of uncharacterized protein complexes and pathways.

    Genome research 2004;14;7;1315-23

  • The novel human platelet septin SEPT8 is an interaction partner of SEPT4.

    Bläser S, Horn J, Würmell P, Bauer H, Strümpell S, Nurden P, Pagenstecher A, Busse A, Wunderle D, Hainmann I and Zieger B

    Department of Pediatrics and Adolescent Medicine, University Hospital Freiburg, Mathildenstr. 1, D-79106 Freiburg, Germany.

    Septins are a family of GTP-binding proteins, which are essential for active membrane movement such as cytokinesis and vesicle trafficking. In non-dividing cells (such as platelets and neurons) septins are implicated in exocytosis. Platelets from a SEPT5 knockout mouse showed an altered serotonin secretion and platelet aggregation, suggesting that SEPT5 is involved in secretion in platelets. Septins form complexes consisting of multiple septin polypeptides. Using the yeast two-hybrid system we had demonstrated that SEPT5 partners with SEPT8. The aim of this study was to identify other interaction partners of the human platelet septin SEPT8. Using the yeast two-hybrid system with SEPT8 as bait protein we identified the human septin SEPT4 as an interaction partner of SEPT8. The interaction between SEPT4 and SEPT8 was confirmed by immunoprecipitation. Expression analysis revealed that SEPT4 is also expressed in human platelets. Thus, SEPT4 is the third described platelet septin besides SEPT5 and SEPT8. Transmission electron microscopy of platelets revealed that SEPT8 and SEPT4 are localized surrounding alpha-granules (as it had been shown for the septin SEPT5) suggesting that the three septins may be components of the septin complex in platelets and contribute in such a way to platelet biology. Activation of platelets by agonists resulted in the translocation of SEPT4 and SEPT8 to the platelet surface indicating a possible functional role of these proteins in platelet granular secretion.

    Thrombosis and haemostasis 2004;91;5;959-66

  • Complete sequencing and characterization of 21,243 full-length human cDNAs.

    Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T and Sugano S

    Helix Research Institute, 1532-3 Yana, Kisarazu, Chiba 292-0812, Japan.

    As a base for human transcriptome and functional genomics, we created the "full-length long Japan" (FLJ) collection of sequenced human cDNAs. We determined the entire sequence of 21,243 selected clones and found that 14,490 cDNAs (10,897 clusters) were unique to the FLJ collection. About half of them (5,416) seemed to be protein-coding. Of those, 1,999 clusters had not been predicted by computational methods. The distribution of GC content of nonpredicted cDNAs had a peak at approximately 58% compared with a peak at approximately 42%for predicted cDNAs. Thus, there seems to be a slight bias against GC-rich transcripts in current gene prediction procedures. The rest of the cDNAs unique to the FLJ collection (5,481) contained no obvious open reading frames (ORFs) and thus are candidate noncoding RNAs. About one-fourth of them (1,378) showed a clear pattern of splicing. The distribution of GC content of noncoding cDNAs was narrow and had a peak at approximately 42%, relatively low compared with that of protein-coding cDNAs.

    Nature genetics 2004;36;1;40-5

  • A genome annotation-driven approach to cloning the human ORFeome.

    Collins JE, Wright CL, Edwards CA, Davis MP, Grinham JA, Cole CG, Goward ME, Aguado B, Mallya M, Mokrab Y, Huckle EJ, Beare DM and Dunham I

    The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.

    We have developed a systematic approach to generating cDNA clones containing full-length open reading frames (ORFs), exploiting knowledge of gene structure from genomic sequence. Each ORF was amplified by PCR from a pool of primary cDNAs, cloned and confirmed by sequencing. We obtained clones representing 70% of genes on human chromosome 22, whereas searching available cDNA clone collections found at best 48% from a single collection and 60% for all collections combined.

    Genome biology 2004;5;10;R84

  • Dopamine-dependent neurodegeneration in rats induced by viral vector-mediated overexpression of the parkin target protein, CDCrel-1.

    Dong Z, Ferger B, Paterna JC, Vogel D, Furler S, Osinde M, Feldon J and Büeler H

    Institute of Molecular Biology, University of Zurich, 8057 Zurich, Switzerland.

    Mutations in the parkin gene are linked to autosomal-recessive juvenile parkinsonism (AR-JP). Parkin functions as a ubiquitin protein ligase in the degradation of several proteins, including the neuron-specific septin CDCrel-1. AR-JP-associated parkin mutations inhibit ubiquitination and degradation of CDCrel-1 and other parkin target proteins. Here we show that recombinant adeno-associated virus-mediated CDCrel-1 gene transfer to the substantia nigra of rats results in a rapid onset (6-10 days) of nigral and striatal CDCrel-1 expression that is followed by a progressive loss of nigral dopaminergic neurons and a decline of the striatal dopamine levels. In contrast, neurons of the globus pallidus are spared from CDCrel-1 toxicity. Furthermore, CDCrel-1 inhibits the release of dopamine from stably-transfected PC12 cells, and pharmacological inhibition of tyrosine hydroxylase and dopamine synthesis in rats prevents CDCrel-1-induced nigral neurodegeneration. These results show that CDCrel-1 overexpression exerts dopamine-dependent neurotoxicity and suggest that inhibition of dopamine secretion by CDCrel-1 may contribute to the development of AR-JP.

    Proceedings of the National Academy of Sciences of the United States of America 2003;100;21;12438-43

  • SEPT5_v2 is a parkin-binding protein.

    Choi P, Snyder H, Petrucelli L, Theisler C, Chong M, Zhang Y, Lim K, Chung KK, Kehoe K, D'Adamio L, Lee JM, Cochran E, Bowser R, Dawson TM and Wolozin B

    Department of Pharmacology, Loyola University Medical Center, Bldg 102/3634, 2160 S 1st Ave, Maywood, IL 60153, USA.

    Mutations in parkin are associated with various inherited forms of Parkinson's disease (PD). Parkin is a ubiquitin ligase enzyme that catalyzes the covalent attachment of ubiquitin moieties onto substrate proteins destined for proteasomal degradation. The substrates of parkin-mediated ubiquitination have yet to be completely identified. Using a yeast two-hybrid screen, we isolated the septin, human SEPT5_v2 (also known as cell division control-related protein 2), as a putative parkin-binding protein. SEPT5_v2 is highly homologous to another septin, SEPT5, which was recently identified as a target for parkin-mediated ubiquitination. SEPT5_v2 binds to parkin at the amino terminus and in the ring finger domains. Several lines of evidence have validated the putative link between parkin and SEPT5_v2. Parkin co-precipitates with SEPT5_v2 from human substantia nigra lysates. Parkin ubiquitinates SEPT5_v2 in vitro, and both SEPT5_v1 and SEPT5_v2 accumulate in brains of patients with ARJP, suggesting that parkin is essential for the normal metabolism of these proteins. These findings suggest that an important relationship exists between parkin and septins.

    Brain research. Molecular brain research 2003;117;2;179-89

  • Isolation of new splice isoforms, characterization and expression analysis of the human septin SEPT8 (KIAA0202).

    Bläser S, Jersch K, Hainmann I, Zieger W, Wunderle D, Busse A and Zieger B

    Department of Pediatrics and Adolescent Medicine, University of Freiburg, Children's Hospital, Mathildenstrasse 1, D-79106 Freiburg, Germany.

    SEPT8 (KIAA0202) is a member of the highly conserved septin family. Septins are membrane-associated GTPases which are involved in cytokinesis and cellular morphogenesis. Using the yeast two-hybrid system and the glutathione-S-transferase pull-down assay we previously had identified the SEPT8 (KIAA0202) as interaction partner of the human septin SEPT5 (cell division cycle related-1, CDCrel-1). Since the complete cDNA sequence of the human septin SEPT8 (KIAA0202) was not known at that time, we isolated new 5' and 3' cDNA sequence of SEPT8 (KIAA0202) by screening three different cDNA libraries. In addition, we performed the characterization of SEPT8 (KIAA0202) and identified new splice variants of SEPT8 (KIAA0202). The expression pattern of SEPT8 (KIAA0202) and its interaction partner SEPT5 (CDCrel-1) is illustrated.

    Gene 2003;312;313-20

  • Human septin-septin interaction: CDCrel-1 partners with KIAA0202.

    Bläser S, Jersch K, Hainmann I, Wunderle D, Zgaga-Griesz A, Busse A and Zieger B

    Children's Hospital, University of Freiburg, Mathildenstr. 1, Freiburg, Germany.

    Septins are evolutionary conserved cytoskeletal GTPases forming heteropolymer complexes involved in cytokinesis and other cellular processes. CDCrel-1 (cell division cycle related-1) is a recently cloned and characterized human septin which is highly expressed in non-dividing cells, such as neurons. Using a yeast two-hybrid system we demonstrate that CDCrel-1 partners with another uncharacterized human septin, KIAA0202. The interaction of CDCrel-1 and KIAA0202 was confirmed in the human leukemia cell line K-562 using pull-down assays with a KIAA0202-glutathione S-transferase fusion protein and by immunoprecipitation of the CDCrel-1-KIAA0202 complex with an anti-KIAA0202 antibody. Expression studies of the two human septins revealed a concomitant expression of both proteins in certain cells.

    FEBS letters 2002;519;1-3;169-72

  • A prototypic platelet septin and its participation in secretion.

    Dent J, Kato K, Peng XR, Martinez C, Cattaneo M, Poujol C, Nurden P, Nurden A, Trimble WS and Ware J

    Division of Experimental Hemostasis and Thrombosis, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.

    Studies are presented characterizing platelet CDCrel-1, a protein expressed to high levels by megakaryocytes and belonging to a family of conserved proteins, termed septin. Septin filaments originally were identified in yeast as essential for budding but have become increasingly associated with processes in higher eukaryotic cells involving active membrane movement such as cytokinesis and vesicle trafficking. Direct proof of an in vivo function for septins in higher eukaryotes is limited to the characterization of the Drosophila septin, termed PNUT. We present studies identifying platelet CDCrel-1 as a protein kinase substrate in the presence of known platelet agonists. The immunopurification of CDCrel-1 revealed it to be part of a macromolecular complex containing a protein involved in platelet secretion, syntaxin 4. Moreover, CDCrel-1 was localized in situ to areas surrounding platelet-storage granules. The relevance of CDCrel-1 to normal platelet function was established with the characterization of platelets from a CDCrel-1(Null) mouse. As compared with platelets from wild-type littermates, CDCrel-1(Null) platelets aggregate and release stored [14C]serotonin in the presence of subthreshold levels of collagen. These results provide new insights into the mechanisms regulating platelet secretion and identify platelet septins as a protein family contributing to membrane trafficking within the megakaryocyte and platelet.

    Funded by: NHLBI NIH HHS: HL50545, R01 HL050545

    Proceedings of the National Academy of Sciences of the United States of America 2002;99;5;3064-9

  • A novel mitochondrial septin-like protein, ARTS, mediates apoptosis dependent on its P-loop motif.

    Larisch S, Yi Y, Lotan R, Kerner H, Eimerl S, Tony Parks W, Gottfried Y, Birkey Reffey S, de Caestecker MP, Danielpour D, Book-Melamed N, Timberg R, Duckett CS, Lechleider RJ, Steller H, Orly J, Kim SJ and Roberts AB

    Pathology Department, Rambam Medical Center, Haifa, Israel.

    Here we describe a protein product of the human septin H5/PNUTL2/CDCrel2b gene, which we call ARTS (for apoptosis-related protein in the TGF-beta signalling pathway). ARTS is expressed in many cells and acts to enhance cell death induced by TGF-beta or, to a lesser extent, by other apoptotic agents. Unlike related septin gene products, ARTS is localized to mitochondria and translocates to the nucleus when apoptosis occurs. Mutation of the P-loop of ARTS abrogates its competence to activate caspase 3 and to induce apoptosis. Taken together, these observations expand the functional attributes of septins previously described as having roles in cytokinesis and cellular morphogenesis.

    Nature cell biology 2000;2;12;915-21

  • Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1.

    Zhang Y, Gao J, Chung KK, Huang H, Dawson VL and Dawson TM

    Departments of Neurology, Neuroscience, and Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287-0005, USA.

    Parkinson's disease is a common neurodegenerative disorder in which familial-linked genes have provided novel insights into the pathogenesis of this disorder. Mutations in Parkin, a ring-finger-containing protein of unknown function, are implicated in the pathogenesis of autosomal recessive familial Parkinson's disease. Here, we show that Parkin binds to the E2 ubiquitin-conjugating human enzyme 8 (UbcH8) through its C-terminal ring-finger. Parkin has ubiquitin-protein ligase activity in the presence of UbcH8. Parkin also ubiquitinates itself and promotes its own degradation. We also identify and show that the synaptic vesicle-associated protein, CDCrel-1, interacts with Parkin through its ring-finger domains. Furthermore, Parkin ubiquitinates and promotes the degradation of CDCrel-1. Familial-linked mutations disrupt the ubiquitin-protein ligase function of Parkin and impair Parkin and CDCrel-1 degradation. These results suggest that Parkin functions as an E3 ubiquitin-protein ligase through its ring domains and that it may control protein levels via ubiquitination. The loss of Parkin's ubiquitin-protein ligase function in familial-linked mutations suggests that this may be the cause of familial autosomal recessive Parkinson's disease.

    Funded by: NINDS NIH HHS: NS38377, P50 NS038377

    Proceedings of the National Academy of Sciences of the United States of America 2000;97;24;13354-9

  • The septin CDCrel-1 binds syntaxin and inhibits exocytosis.

    Beites CL, Xie H, Bowser R and Trimble WS

    Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada.

    Septins are GTPases required for the completion of cytokinesis in diverse organisms, yet their roles in cytokinesis or other cellular processes remain unknown. Here we describe studies of a newly identified septin, CDCrel-1, which is predominantly expressed in the nervous system. This protein was associated with membrane fractions, and a significant fraction of the protein copurified and coprecipitated with synaptic vesicles. In detergent extracts, CDCrel-1 and another septin, Nedd5, immunoprecipitated with the SNARE protein syntaxin by directly binding to syntaxin via the SNARE interaction domain. Transfection of HIT-T15 cells with wild-type CDCrel-1 inhibited secretion, whereas GTPase dominant-negative mutants enhanced secretion. These data suggest that septins may regulate vesicle dynamics through interactions with syntaxin.

    Funded by: NIA NIH HHS: AG13208

    Nature neuroscience 1999;2;5;434-9

  • Localization of a novel septin protein, hCDCrel-1, in neurons of human brain.

    Caltagarone J, Rhodes J, Honer WG and Bowser R

    Department of Pathology, University of Pittsburgh School of Medicine, PA 15261, USA.

    Synaptic function is critical for cell-cell communication and the characterization of proteins that function during vesicle formation, transport and fusion events will yield further insight into the mechanisms of synaptic transmission. We have cloned and characterized a gene product expressed in human brain called hCDCrel-1. This protein is a new member of the septin family of gene products that functions during cytokinesis in lower eukaryotes. In this study we characterize the expression of the hCDCrel-1 gene and localize the hCDCrel-1 protein to neurons in adult human brain. hCDCrel-1 co-purifies with SNAP-25 and synaptophysin marked synaptosomes, suggesting a novel function for this gene family in the brain. Our data indicate that members of the septin family of proteins may function in synaptic vesicle transport, fusion or recycling events in the human brain.

    Neuroreport 1998;9;12;2907-12

  • Structure and expression of the human septin gene HCDCREL-1.

    Yagi M, Zieger B, Roth GJ and Ware J

    Research, Department of Veterans Affairs Puget Sound Health Care Center, Seattle, WA 98108, USA. myagi@u.washington.edu

    Septins are a family of highly conserved filament-forming proteins that have been shown to mediate cytokinesis and cytoskeletal organization in fungi and Drosophila. The gene encoding the human septin family member HCDCREL-1 has been shown to be transcribed from a locus immediately adjacent to that of the platelet glycoprotein (GP) Ib b. The HCDCREL-1 gene possesses a non-consensus polyadenylation signal that apparently is not efficiently utilized, resulting in the expression of a readthrough transcript also containing the platelet GPIb beta coding region. As a first step in understanding the regulation and function of HCDCREL-1, we have analyzed the structure of this gene and characterized its expression in a variety of human cells. Our results indicate that the gene is expressed at high levels in platelets and neural tissue, and is transcriptionally complex.

    Funded by: NHLBI NIH HHS: HL39947, HL50545

    Gene 1998;212;2;229-36

  • Subunit composition, protein interactions, and structures of the mammalian brain sec6/8 complex and septin filaments.

    Hsu SC, Hazuka CD, Roth R, Foletti DL, Heuser J and Scheller RH

    Howard Hughes Medical Institute, Department of Molecular and Cellular Physiology, Stanford University School of Medicine, California 94305, USA.

    Both the sec6/8 complex and septin filaments have been implicated in directing vesicles and proteins to sites of active membrane addition in yeast. The rat brain sec6/8 complex coimmunoprecipitates with a filament composed of four mammalian septins, suggesting an interaction between these complexes. One of the septins, CDC10, displays broad subcellular and tissue distributions and is found in postmitotic neurons as well as dividing cells. Electron microscopic studies showed that the purified rat brain septins form filaments of 8.25 nm in diameter; the lengths of the filaments are multiples of 25 nm. Glutaraldehyde-fixed rat brain sec6/8 complex adopts a conformation resembling the letter "T" or "Y". The sec6/8 and septin complexes likely play an important role in trafficking vesicles and organizing proteins at the plasma membrane of neurons.

    Neuron 1998;20;6;1111-22

  • t(11;22)(q23;q11.2) In acute myeloid leukemia of infant twins fuses MLL with hCDCrel, a cell division cycle gene in the genomic region of deletion in DiGeorge and velocardiofacial syndromes.

    Megonigal MD, Rappaport EF, Jones DH, Williams TM, Lovett BD, Kelly KM, Lerou PH, Moulton T, Budarf ML and Felix CA

    Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

    We examined the MLL genomic translocation breakpoint in acute myeloid leukemia of infant twins. Southern blot analysis in both cases showed two identical MLL gene rearrangements indicating chromosomal translocation. The rearrangements were detectable in the second twin before signs of clinical disease and the intensity relative to the normal fragment indicated that the translocation was not constitutional. Fluorescence in situ hybridization with an MLL-specific probe and karyotype analyses suggested t(11;22)(q23;q11. 2) disrupting MLL. Known 5' sequence from MLL but unknown 3' sequence from chromosome band 22q11.2 formed the breakpoint junction on the der(11) chromosome. We used panhandle variant PCR to clone the translocation breakpoint. By ligating a single-stranded oligonucleotide that was homologous to known 5' MLL genomic sequence to the 5' ends of BamHI-digested DNA through a bridging oligonucleotide, we formed the stem-loop template for panhandle variant PCR which yielded products of 3.9 kb. The MLL genomic breakpoint was in intron 7. The sequence of the partner DNA from band 22q11.2 was identical to the hCDCrel (human cell division cycle related) gene that maps to the region commonly deleted in DiGeorge and velocardiofacial syndromes. Both MLL and hCDCrel contained homologous CT, TTTGTG, and GAA sequences within a few base pairs of their respective breakpoints, which may have been important in uniting these two genes by translocation. Reverse transcriptase-PCR amplified an in-frame fusion of MLL exon 7 to hCDCrel exon 3, indicating that an MLL-hCDCrel chimeric mRNA had been transcribed. Panhandle variant PCR is a powerful strategy for cloning translocation breakpoints where the partner gene is undetermined. This application of the method identified a region of chromosome band 22q11.2 involved in both leukemia and a constitutional disorder.

    Funded by: NCI NIH HHS: 1R29CA66140-03; NHLBI NIH HHS: HL51533; NIDCD NIH HHS: DC02027, P01 DC002027

    Proceedings of the National Academy of Sciences of the United States of America 1998;95;11;6413-8

  • A human gene similar to Drosophila melanogaster peanut maps to the DiGeorge syndrome region of 22q11.

    McKie JM, Sutherland HF, Harvey E, Kim UJ and Scambler PJ

    Molecular Medicine Unit, Institute of Child Health, London, UK.

    A Drosophila-related expressed sequence tag (DRES) with sequence similarity to the peanut gene has previously been localized to human chromosome 22q11. We have isolated the cDNA corresponding to this DRES and show that it is a novel member of the family of septin genes, which encode proteins with GTPase activity thought to interact during cytokinesis. The predicted protein has P-loop nucleotide binding and GTPase motifs. The gene, which we call PNUTL1, maps to the region of 22q11.2 frequently deleted in DiGeorge and velo-cardio-facial syndromes and is particularly highly expressed in the brain. The mouse homologue, Pnutl1, maps to MMU16 adding to the growing number of genes from the DiGeorge syndrome region that map to this chromosome.

    Funded by: Wellcome Trust

    Human genetics 1997;101;1;6-12

  • Alternative expression of platelet glycoprotein Ib(beta) mRNA from an adjacent 5' gene with an imperfect polyadenylation signal sequence.

    Zieger B, Hashimoto Y and Ware J

    Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.

    Glycoprotein (GP) Ib is a major component of the platelet membrane receptor for von Willebrand factor, designated the GP Ib-IX-V complex. GP Ib is composed of two subunits (GP Ib(alpha) and GP Ib(beta)) each synthesized from separate genes. The 206 amino acid precursor of GP Ib(beta) is synthesized from a 1.0-kb mRNA expressed by megakaryocytes and was originally characterized from cDNA clones of human erythroleukemic (HEL) cell mRNA, a cell line exhibiting megakaryocytic-like properties. The cell line CHRF-288-11 also exhibits megakaryocytic-like properties, but synthesizes two related GP Ib(beta) mRNA species of 3.5 and 1.0 kb. We performed cDNA cloning experiments to identify the origin of the 3.5-kb transcript and determine its relationship to the 1.0-kb GP Ib(beta) mRNA found in megakaryocytes, platelets, and HEL cells. Our cloning experiments demonstrate that the longer transcript results from a nonconsensus polyadenylation recognition sequence, 5'AACAAT3', within a separate gene located upstream to the platelet GP Ib(beta) gene. In the absence of normal polyadenylation the more 5' gene uses the polyadenylation site within its 3' neighbor, the platelet GP Ib(beta) gene. This newly identified 5' gene contains an open reading frame encoding 369 amino acids with a high degree of sequence similarity to an expanding family of GTP-binding proteins.

    Funded by: NHLBI NIH HHS: HL50545

    The Journal of clinical investigation 1997;99;3;520-5

  • Structural characterization and chromosomal location of the gene encoding human platelet glycoprotein Ib beta.

    Yagi M, Edelhoff S, Disteche CM and Roth GJ

    Hematology Section, Seattle Veterans Administration Medical Center, Washington 98108.

    Human platelet glycoprotein Ib beta (GPIb beta) (M(r) 22,000) is part of the GPIb-V-IX system that constitutes the receptor for von Willebrand factor and mediates platelet adhesion in the arterial circulation. The four members of the receptor (GPs Ib alpha, Ib beta, V, and IX) share structural and functional features. Individually, GPIb beta contributes to surface expression of the receptor and participates in transmembrane signaling through phosphorylation of its intracellular domain. To define the structure of the GPIb beta gene, a cosmid clone from a human genomic library was analyzed. The transcriptional start site was located by both primer extension and the "anchored" polymerase chain reaction. Similar to the genes for Ib alpha, V, and IX, the Ib beta gene is compact with a single 274-base intron inserted into the 5' end of the open reading frame. The 5'-flanking region of the gene contains both GATA and ets sites that are also found in the 5' promoter regions of other described megakaryocyte/platelet genes. The GPIb beta gene was localized to chromosome 22q11.2 by fluorescence in situ hybridization. The GPIb beta gene has a simple structure, similar to that of other described megakaryocyte/platelet genes, including those of the GPIb-V-IX system.

    Funded by: NHLBI NIH HHS: HL39947

    The Journal of biological chemistry 1994;269;26;17424-7

Gene lists (8)

Gene List Source Species Name Description Gene count
L00000009 G2C Homo sapiens Human PSD Human orthologues of mouse PSD adapted from Collins et al (2006) 1080
L00000013 G2C Homo sapiens Human mGluR5 Human orthologues of mouse mGluR5 complex adapted from Collins et al (2006) 52
L00000016 G2C Homo sapiens Human PSP Human orthologues of mouse PSP adapted from Collins et al (2006) 1121
L00000049 G2C Homo sapiens TAP-PSD-95-CORE TAP-PSD-95 pull-down core list (ortho) 120
L00000059 G2C Homo sapiens BAYES-COLLINS-HUMAN-PSD-CONSENSUS Human cortex PSD consensus 748
L00000061 G2C Homo sapiens BAYES-COLLINS-MOUSE-PSD-CONSENSUS Mouse cortex PSD consensus (ortho) 984
L00000069 G2C Homo sapiens BAYES-COLLINS-HUMAN-PSD-FULL Human cortex biopsy PSD full list 1461
L00000071 G2C Homo sapiens BAYES-COLLINS-MOUSE-PSD-FULL Mouse cortex PSD full list (ortho) 1556
© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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