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Definição e significado de CDC6

Definição

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CDC6

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Cell division cycle 6 homolog (S. cerevisiae)
Identifiers
SymbolsCDC6; CDC18L; HsCDC18; HsCDC6
External IDsOMIM602627 MGI1345150 HomoloGene68172 GeneCards: CDC6 Gene
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez99023834
EnsemblENSG00000094804n/a
UniProtQ99741n/a
RefSeq (mRNA)NM_001254NM_001025779
RefSeq (protein)NP_001245NP_001020950
Location (UCSC)Chr 17:
35.7 - 35.71 Mb
n/a
PubMed search[1][2]

Cell division control protein 6 homolog is a protein that in humans is encoded by the CDC6 gene.[1][2]

The protein encoded by this gene is highly similar to Saccharomyces cerevisiae Cdc6, a protein essential for the initiation of DNA replication. This protein functions as a regulator at the early steps of DNA replication. It localizes in cell nucleus during cell cycle G1, but translocates to the cytoplasm at the start of S phase. The subcellular translocation of this protein during cell cycle is regulated through its phosphorylation by Cyclin-dependent kinases. Transcription of this protein was reported to be regulated in response to mitogenic signals through transcriptional control mechanism involving E2F proteins.[3]

Contents

Interactions

CDC6 has been shown to interact with ORC1L,[4][2] ORC2L,[4][5] Cyclin A2,[6][2] PPP2R3B,[7] MCM3,[8][5] PPP2R3A,[9] MCM7[4][8] and PSKH1.[6]

See also

References

  1. ^ Williams RS, Shohet RV, Stillman B (Feb 1997). [Expression error: Missing operand for > "A human protein related to yeast Cdc6p"]. Proc Natl Acad Sci U S A 94 (1): 142–7. PMID 8990175. 
  2. ^ a b c Saha P, Chen J, Thome KC, Lawlis SJ, Hou ZH, Hendricks M, Parvin JD, Dutta A (May 1998). [Expression error: Missing operand for > "Human CDC6/Cdc18 associates with Orc1 and cyclin-cdk and is selectively eliminated from the nucleus at the onset of S phase"]. Mol Cell Biol 18 (5): 2758–67. PMID 9566895. 
  3. ^ "Entrez Gene: CDC6 cell division cycle 6 homolog (S. cerevisiae)". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=990. 
  4. ^ a b c Kneissl, Margot; Pütter Vera, Szalay Aladar A, Grummt Friedrich (Mar. 2003). [Expression error: Missing operand for > "Interaction and assembly of murine pre-replicative complex proteins in yeast and mouse cells"]. J. Mol. Biol. (England) 327 (1): 111–28. ISSN 0022-2836. PMID 12614612. 
  5. ^ a b Méndez, J; Stillman B (Nov. 2000). [Expression error: Missing operand for > "Chromatin association of human origin recognition complex, cdc6, and minichromosome maintenance proteins during the cell cycle: assembly of prereplication complexes in late mitosis"]. Mol. Cell. Biol. (UNITED STATES) 20 (22): 8602–12. ISSN 0270-7306. PMID 11046155. 
  6. ^ a b Petersen, B O; Lukas J, Sørensen C S, Bartek J, Helin K (Jan. 1999). [Expression error: Missing operand for > "Phosphorylation of mammalian CDC6 by cyclin A/CDK2 regulates its subcellular localization"]. EMBO J. (ENGLAND) 18 (2): 396–410. doi:10.1093/emboj/18.2.396. ISSN 0261-4189. PMID 9889196. 
  7. ^ Yan, Z; Fedorov S A, Mumby M C, Williams R S (Feb. 2000). [Expression error: Missing operand for > "PR48, a novel regulatory subunit of protein phosphatase 2A, interacts with Cdc6 and modulates DNA replication in human cells"]. Mol. Cell. Biol. (UNITED STATES) 20 (3): 1021–9. ISSN 0270-7306. PMID 10629059. 
  8. ^ a b Fujita, M; Yamada C, Goto H, Yokoyama N, Kuzushima K, Inagaki M, Tsurumi T (Sep. 1999). [Expression error: Missing operand for > "Cell cycle regulation of human CDC6 protein. Intracellular localization, interaction with the human mcm complex, and CDC2 kinase-mediated hyperphosphorylation"]. J. Biol. Chem. (UNITED STATES) 274 (36): 25927–32. ISSN 0021-9258. PMID 10464337. 
  9. ^ Davis, Anthony J; Yan Zhen, Martinez Bobbie, Mumby Marc C (Jun. 2008). [Expression error: Missing operand for > "Protein phosphatase 2A is targeted to cell division control protein 6 by a calcium-binding regulatory subunit"]. J. Biol. Chem. (United States) 283 (23): 16104–14. doi:10.1074/jbc.M710313200. ISSN 0021-9258. PMID 18397887. 

Further reading

  • Yan Z, DeGregori J, Shohet R, et al. (1998). [Expression error: Missing operand for > "Cdc6 is regulated by E2F and is essential for DNA replication in mammalian cells."]. Proc. Natl. Acad. Sci. U.S.A. 95 (7): 3603–8. doi:10.1073/pnas.95.7.3603. PMID 9520412. 
  • Hateboer G, Wobst A, Petersen BO, et al. (1998). [Expression error: Missing operand for > "Cell cycle-regulated expression of mammalian CDC6 is dependent on E2F."]. Mol. Cell. Biol. 18 (11): 6679–97. PMID 9774682. 
  • Ohtani K, Tsujimoto A, Ikeda M, Nakamura M (1998). [Expression error: Missing operand for > "Regulation of cell growth-dependent expression of mammalian CDC6 gene by the cell cycle transcription factor E2F."]. Oncogene 17 (14): 1777–85. doi:10.1038/sj.onc.1202105. PMID 9778043. 
  • Stoeber K, Mills AD, Kubota Y, et al. (1999). [Expression error: Missing operand for > "Cdc6 protein causes premature entry into S phase in a mammalian cell-free system."]. Embo J. 17 (24): 7219–29. doi:10.1093/emboj/17.24.7219. PMID 9857179. 
  • Petersen BO, Lukas J, Sørensen CS, et al. (1999). [Expression error: Missing operand for > "Phosphorylation of mammalian CDC6 by cyclin A/CDK2 regulates its subcellular localization."]. Embo J. 18 (2): 396–410. doi:10.1093/emboj/18.2.396. PMID 9889196. 
  • van Hannen EJ, Zwart G, van Agterveld MP, et al. (1999). [Expression error: Missing operand for > "Changes in bacterial and eukaryotic community structure after mass lysis of filamentous cyanobacteria associated with viruses."]. Appl. Environ. Microbiol. 65 (2): 795–801. PMID 9925618. 
  • Takei Y, Yamamoto K, Tsujimoto G (1999). [Expression error: Missing operand for > "Identification of the sequence responsible for the nuclear localization of human Cdc6."]. FEBS Lett. 447 (2-3): 292–6. doi:10.1016/S0014-5793(99)00306-3. PMID 10214964. 
  • Jiang W, Wells NJ, Hunter T (1999). [Expression error: Missing operand for > "Multistep regulation of DNA replication by Cdk phosphorylation of HsCdc6."]. Proc. Natl. Acad. Sci. U.S.A. 96 (11): 6193–8. doi:10.1073/pnas.96.11.6193. PMID 10339564. 
  • Fujita M, Yamada C, Goto H, et al. (1999). [Expression error: Missing operand for > "Cell cycle regulation of human CDC6 protein. Intracellular localization, interaction with the human mcm complex, and CDC2 kinase-mediated hyperphosphorylation."]. J. Biol. Chem. 274 (36): 25927–32. doi:10.1074/jbc.274.36.25927. PMID 10464337. 
  • Yan Z, Fedorov SA, Mumby MC, Williams RS (2000). [Expression error: Missing operand for > "PR48, a novel regulatory subunit of protein phosphatase 2A, interacts with Cdc6 and modulates DNA replication in human cells."]. Mol. Cell. Biol. 20 (3): 1021–9. doi:10.1128/MCB.20.3.1021-1029.2000. PMID 10629059. 
  • Takahashi Y, Rayman JB, Dynlacht BD (2000). [Expression error: Missing operand for > "Analysis of promoter binding by the E2F and pRB families in vivo: distinct E2F proteins mediate activation and repression."]. Genes Dev. 14 (7): 804–16. PMID 10766737. 
  • Takayama M, Taira T, Iguchi-Ariga SM, Ariga H (2000). [Expression error: Missing operand for > "CDC6 interacts with c-Myc to inhibit E-box-dependent transcription by abrogating c-Myc/Max complex."]. FEBS Lett. 477 (1-2): 43–8. doi:10.1016/S0014-5793(00)01756-7. PMID 10899308. 
  • Petersen BO, Wagener C, Marinoni F, et al. (2000). [Expression error: Missing operand for > "Cell cycle- and cell growth-regulated proteolysis of mammalian CDC6 is dependent on APC-CDH1."]. Genes Dev. 14 (18): 2330–43. doi:10.1101/gad.832500. PMID 10995389. 
  • Méndez J, Stillman B (2000). [Expression error: Missing operand for > "Chromatin association of human origin recognition complex, cdc6, and minichromosome maintenance proteins during the cell cycle: assembly of prereplication complexes in late mitosis."]. Mol. Cell. Biol. 20 (22): 8602–12. doi:10.1128/MCB.20.22.8602-8612.2000. PMID 11046155. 
  • Delmolino LM, Saha P, Dutta A (2001). [Expression error: Missing operand for > "Multiple mechanisms regulate subcellular localization of human CDC6."]. J. Biol. Chem. 276 (29): 26947–54. doi:10.1074/jbc.M101870200. PMID 11346650. 
  • Fujita M, Ishimi Y, Nakamura H, et al. (2002). [Expression error: Missing operand for > "Nuclear organization of DNA replication initiation proteins in mammalian cells."]. J. Biol. Chem. 277 (12): 10354–61. doi:10.1074/jbc.M111398200. PMID 11779870. 
  • Biermann E, Baack M, Kreitz S, Knippers R (2002). [Expression error: Missing operand for > "Synthesis and turn-over of the replicative Cdc6 protein during the HeLa cell cycle."]. Eur. J. Biochem. 269 (3): 1040–6. doi:10.1046/j.0014-2956.2001.02746.x. PMID 11846807. 
  • Robles LD, Frost AR, Davila M, et al. (2002). [Expression error: Missing operand for > "Down-regulation of Cdc6, a cell cycle regulatory gene, in prostate cancer."]. J. Biol. Chem. 277 (28): 25431–8. doi:10.1074/jbc.M201199200. PMID 12006585. 

Cdc6

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Cdc6
Crystal Structure of CDC6p from P. aerophilum.[1]
Identifiers
SymbolCdc6
Alt. symbolsYJL194W
Entrez853244
PDB1FNN
UniProtP09119
Other data

Cdc6, or Cell Division Cycle 6, is a protein in eukaryotic cells that is studied in the budding yeast Saccharomyces cerevisiae. It is an essential regulator of DNA replication and plays important roles in the activation and maintenance of the checkpoint mechanisms in the cell cycle that coordinate S phase and mitosis. It is part of the pre-replicative complex (pre-RC) and is required for loading Mini Chromosome Maintenance (MCM) proteins onto the DNA, an essential step in the initiation of DNA synthesis. In addition, it’s a member of the family of AAA+ ATPases and highly associated to Orc1p.

Contents

Function

Potential role of Cdc6 at the initiation of DNA replication.[2]

Cdc6p is an ATP binding protein and a member of the pre-replicative complex (pre-RC) together with the origin recognition complex (ORC), Cdt1 and the MCM complex (containing MCM2-7p). Cdc6p assembles after ORC in an ATP dependent manner and is required for loading MCM proteins onto the DNA. Reconstruction of electron microscope images showed that the ORC-Cdc6p complex forms a ring-shaped structure with similar dimensions to those of ring-shaped MCM helicase.[3]It is thought that the Cdc6p-Cdt1 complex uses ATP hydrolysis to thread DNA through the central hole of the MCM doughnut.[4] Mutations in the binding motif of Cdc6p strongly suggest that ATP binding and hydrolysis is essential for its function.[5] The minimal requirement for DNA binding has been mapped within its 47-amino acid sequence.[6] Furthermore Cdc6 indirectly inhibits activation of the p34cdc2/CDC28 M phase kinase, thus nuclear division is suppressed.[7]

Regulation

Cdc6p is normally present at high levels during the G1 phase of the cell cycle. This is partly because the CDC6 gene is only transcribed during G1 phase. On the onset of the S phase, Cdc6p gets phosphorylated by the Cdc28-Clb5-Clb6 complex (Cdk1) and consequently becoming inactivated. This has been shown by introducing mutations in Cdc6p at the consensus sites for Cdk1 phosphorylation (near the N-terminus) which inhibit degradation. The phosphorylation can furthermore be catalyzed by Cdc28-Cln. The inactivated Cdc6p is then targeted for degradation by SCFCDC4-dependent ubiquitinylation and afterwards degraded by the proteosome. Thus, the regulation of Cdc6p is tightly correlated to the activity of Cdk1 and since Cdk1-activity is oscillating once per cell cycle, the accumulation and degradation of Cdc6p also oscillates.

Two states can be distinguished. In the first state (during G1 phase) Cdk1-activity is low, Cdc6p can accumulate, hence the pre-RC can be formed but not activated. In the second state Cdk1-activity is high, Cdc6p becomes inactivated, hence the pre-RC is activated but not formed. This change assures that DNA replication is performed only once per cell cycle. It has been shown that overexpression of Cdc6p does not induce re-replication in cognate cells, probably due to inhibition through CDK that resets the cellcycle clock to G1. Nevertheless it has been suggested that regulation of Cdc6p is one of several redundant mechanisms that prevent re-replication of the DNA in eukaryotic cells.[8]

Structure

Crystal Structure of CDC6p from Pyrobaculum aerophilum. Domain I in green, domain II in blue and domain III in red. Beta-sheets are shown in orange.

The crystallographic structure of a Cdc6p/Orc1-related protein from Pyrobaculum aerophilum (see Pyrobaculum) has been solved and three structural domains have been identified. Domain I and II form the ATP binding/hydrolysis site and are similar Similar to other AAA+ ATPases. Domain III is structurally related to a winged-helix domain, thus may interact with origin DNA. From studies with E. coli γ clamp loading complex, it was suggested that domain III mediates protein-protein interactions with other AAA+ ATPases in the pre-RC, thus suggesting that the Cdc6p builds a homodimer in its native form. The domains I and II form a cashew-shaped molecule that bind ATP in the cleft and additionally build the sensor motif for ATP/ADP recognition. These domains are also thought to mediate subsequent conformational changes. Nevertheless, the exact functional roles of these domains remain unclear[6].

Disease

It has been shown Cdc6p shows proto-oncogenic activity. Cdc6 overexpression interferes with the expression of INK4/ARF tumor suppressor genes through a mechanism involving the epigenetic modification of chromatin at the INK4/ARF locus. In addition, Cdc6p overexpression in primary cells may promote DNA hyperreplication and induce a senescence response similar to that caused by oncogene activation. These findings indicate that deregulation of CDC6 expression in human cells poses a serious risk of carcinogenesis[2]. Down-regulation of CDC6 in prostate cancer was observed and associated with phenotypic characteristics of aggressive prostate cancer.[9] Furthermore it has beenobserved that Cdc6 is greatly up-regulated in cervical cancer, lung cancer and brain cancer.[10]

See also

References

  1. ^ PDB 1FNNLiu J, Smith CL, DeRyckere D, DeAngelis K, Martin GS, Berger JM (September 2000). [Expression error: Missing operand for > "Structure and function of Cdc6/Cdc18: implications for origin recognition and checkpoint control"]. Mol. Cell 6 (3): 637–48. doi:10.1016/S1097-2765(00)00062-9. PMID 11030343. 
  2. ^ a b Borlado LR, Méndez J (February 2008). [Expression error: Missing operand for > "CDC6: from DNA replication to cell cycle checkpoints and oncogenesis"]. Carcinogenesis 29 (2): 237–43. doi:10.1093/carcin/bgm268. PMID 18048387. 
  3. ^ Speck C, Chen Z, Li H, Stillman B (November 2005). [Expression error: Missing operand for > "ATPase-dependent cooperative binding of ORC and Cdc6 to origin DNA"]. Nat. Struct. Mol. Biol. 12 (11): 965–71. doi:10.1038/nsmb1002. PMID 16228006. 
  4. ^ Jennifer Lippincott-Schwartz; Pollard, Thomas D.; Earnshaw, William (2007). Cell biology. Saunders Elsevier. pp. 766–767. ISBN 1-4160-2255-4. 
  5. ^ Bell SP, Dutta A (2002). [Expression error: Missing operand for > "DNA replication in eukaryotic cells"]. Annu. Rev. Biochem. 71: 333–74. doi:10.1146/annurev.biochem.71.110601.135425. PMID 12045100. 
  6. ^ a b Feng L, Wang B, Driscoll B, Jong A (May 2000). "Identification and characterization of Saccharomyces cerevisiae Cdc6 DNA-binding properties". Mol. Biol. Cell 11 (5): 1673–85. PMID 10793143. PMC 14875. http://www.molbiolcell.org/cgi/content/abstract/11/5/1673. 
  7. ^ Bueno A, Russell P (June 1992). [Expression error: Missing operand for > "Dual functions of CDC6: a yeast protein required for DNA replication also inhibits nuclear division"]. EMBO J. 11 (6): 2167–76. PMID 1600944. 
  8. ^ Drury LS, Perkins G, Diffley JF (October 1997). [Expression error: Missing operand for > "The Cdc4/34/53 pathway targets Cdc6p for proteolysis in budding yeast"]. EMBO J. 16 (19): 5966–76. doi:10.1093/emboj/16.19.5966. PMID 9312054. 
  9. ^ Robles LD, Frost AR, Davila M, Hutson AD, Grizzle WE, Chakrabarti R (July 2002). [Expression error: Missing operand for > "Down-regulation of Cdc6, a cell cycle regulatory gene, in prostate cancer"]. J. Biol. Chem. 277 (28): 25431–8. doi:10.1074/jbc.M201199200. PMID 12006585. 
  10. ^ Lau E, Tsuji T, Guo L, Lu SH, Jiang W (December 2007). [Expression error: Missing operand for > "The role of pre-replicative complex (pre-RC) components in oncogenesis"]. FASEB J. 21 (14): 3786–94. doi:10.1096/fj.07-8900rev. PMID 17690155. 

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