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SIC1  -  Sic1p

Saccharomyces cerevisiae S288c

Synonyms: CDK inhibitor p40, L9449.8, Protein SIC1, SDB25, YLR079W
 
 
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Disease relevance of SIC1

  • In addition, comparison of the different inhibitory patterns obtained using histone H1 or GST (glutathione S-transferase)-pRb (retinoblastoma protein) fusion protein as substrate (the latter of which recognizes both the docking site and the catalytic site of Cdk2-cyclin A) offers interesting suggestions for the inhibitory mechanism of Sic1 [1].
 

High impact information on SIC1

  • Biochemical reconstitution with purified Sic1, a prototype substrate of the Cdc34/SCF ubiquitin ligase, suggests that substrate degradation is essential for triggering the ATP hydrolysis-dependent dissociation and disassembly of the 19S and that this mechanism leads to release of degradation products [2].
  • By using a F72VCdc34 mutant with increased affinity for the RING domain, we demonstrate that release of ubiquitin-charged Cdc34-S - Ub from the RING is essential for ubiquitination of the SCF(Cdc4)-bound substrate Sic1 [3].
  • The low affinity of each CPD motif in Sic1 reflects structural discordance with one or more elements of the Cdc4 binding site [4].
  • Viability of hct1 mutants depends on SIC1 [5].
  • Phosphorylated Sic1p substrate is specifically targeted for ubiquitination by binding to a Cdc4p/Skp1p subcomplex [6].
 

Biological context of SIC1

  • Our data suggest that cell cycle-regulated nuclear accumulation of Swi5 is responsible for the burst of SIC1 transcription at the end of anaphase [7].
  • Cell cycle-regulated proteolysis seems largely responsible for this pattern, but transcriptional control could also contribute; SIC1 RNA accumulates to high levels as cells exit M phase [7].
  • Deletion of SIC1 allows these mutants to replicate. p40SIC1 disappears at the G1/S transition and reappears only after nuclear division [7].
  • Traversal from G1 to S-phase in cycling cells of budding yeast is dependent on the destruction of the S-phase cyclin/CDK inhibitor SIC1 [8].
  • We have shown previously that the Swi5 transcription factor regulates the expression of the SIC1 Cdk inhibitor in late mitosis [9].
 

Anatomical context of SIC1

 

Associations of SIC1 with chemical compounds

  • The effects of glucose on Sic1p levels and DNA replication required Grr1p, a component of the SCF(Grr1p) ubiquitin ligase [11].
  • Here we show by direct mass spectrometry analysis that Sic1, but not a mutant protein whose CK2 phospho-acceptor site has been mutated to alanine, Sic1S201A, is actually phosphorylated in vitro by CK2 on Serine 201 [12].
 

Physical interactions of SIC1

  • The complementary C-terminal segment of SIC1 binds to the S-phase cyclin CLB5, indicating a modular structure for SIC1 [8].
  • We show that fusion of the Cln2 domain to a stabilized form of the cyclin-dependent kinase inhibitor Sic1 (Delta N-Sic1), a substrate of SCF(Cdc4), results in degradation in a phosphorylation-dependent manner [13].
  • During late mitosis, Cdc6 is present at levels comparable with Sic1 and binds specifically to the mitotic cyclin Clb2 [14].
 

Enzymatic interactions of SIC1

  • Cdc4 assembled with Skp1 functions as the receptor that selectively binds phosphorylated Sic1 [15].
  • Pho85 and other G1 Cdks appear to phosphorylate Sic1 at different sites in vivo [16].
  • We found that Ime2 phosphorylates Sic1 at multiple sites in vitro [17].
 

Regulatory relationships of SIC1

  • Exit from mitosis in yeast involves accumulation of the cyclin kinase inhibitor Sic1 as well as cyclin proteolysis mediated by APC/C bound by the activating subunit Cdh1/Hct1 (APC(Cdh1)) [18].
  • Sic1p is negatively regulated by Ime2p kinase, and several observations indicate that glucose inhibits meiotic DNA replication through SCF(Grr1p)-mediated destruction of this kinase [11].
  • The highly conserved protein phosphatase Cdc14 promotes both Clb degradation and Sic1 accumulation [19].
  • Here we show that Hog1 regulates cell cycle progression at the G1 phase by a dual mechanism that involves downregulation of cyclin expression and direct targeting of the CDK-inhibitor protein Sic1 [20].
  • The CKI Sic1 controls the timing of DNA replication by inhibiting Clb-Cdc28 kinase [21].
 

Other interactions of SIC1

  • The fkh1 fkh2 mutant also displays aberrant regulation of the 'SIC1' cluster, whose member genes are expressed in the M-G1 interval and are involved in mitotic exit [22].
  • In mitosis, Cdc28p controls its own S-phase-promoting activity by signaling the destruction of its inhibitor, Sic1p [23].
  • In meiosis, Sic1p destruction is signaled by the meiosis-specific Ime2p protein kinase [23].
  • While the G(1)/S block in both cdc4-12 and cdc4Delta mutants is abolished by the deletion of the SIC1 gene (causing the mutants to be arrested predominantly in G(2)/M), the preanaphase arrest in the cdc4-12 mutant is relieved by the deletion of PDS1 [24].
  • Consistent with Cak1p's role in activating Ime2p, cells lacking Cak1p are deficient in degrading Sic1p [23].
 

Analytical, diagnostic and therapeutic context of SIC1

  • By sequence analysis we found an amino acid stretch centred on Serine201 matching a stringent CK2 consensus site within the C-terminal, inhibitory domain of Sic1 [12].
  • Here we present new evidence, by using specific anti-P-Ser201 antibodies and 2-D gel electrophoresis coupled to MALDI mass spectrometry analysis, that Sic1 is phosphorylated in vivo on Ser201 shortly after its de novo synthesis, during late anaphase in glucose-grown cells [25].

References

  1. The yeast cyclin-dependent kinase inhibitor Sic1 and mammalian p27Kip1 are functional homologues with a structurally conserved inhibitory domain. Barberis, M., De Gioia, L., Ruzzene, M., Sarno, S., Coccetti, P., Fantucci, P., Vanoni, M., Alberghina, L. Biochem. J. (2005) [Pubmed]
  2. ATP hydrolysis-dependent disassembly of the 26S proteasome is part of the catalytic cycle. Babbitt, S.E., Kiss, A., Deffenbaugh, A.E., Chang, Y.H., Bailly, E., Erdjument-Bromage, H., Tempst, P., Buranda, T., Sklar, L.A., Baumler, J., Gogol, E., Skowyra, D. Cell (2005) [Pubmed]
  3. Release of ubiquitin-charged Cdc34-S - Ub from the RING domain is essential for ubiquitination of the SCF(Cdc4)-bound substrate Sic1. Deffenbaugh, A.E., Scaglione, K.M., Zhang, L., Moore, J.M., Buranda, T., Sklar, L.A., Skowyra, D. Cell (2003) [Pubmed]
  4. Structural basis for phosphodependent substrate selection and orientation by the SCFCdc4 ubiquitin ligase. Orlicky, S., Tang, X., Willems, A., Tyers, M., Sicheri, F. Cell (2003) [Pubmed]
  5. Yeast Hct1 is a regulator of Clb2 cyclin proteolysis. Schwab, M., Lutum, A.S., Seufert, W. Cell (1997) [Pubmed]
  6. A complex of Cdc4p, Skp1p, and Cdc53p/cullin catalyzes ubiquitination of the phosphorylated CDK inhibitor Sic1p. Feldman, R.M., Correll, C.C., Kaplan, K.B., Deshaies, R.J. Cell (1997) [Pubmed]
  7. The transcription factor Swi5 regulates expression of the cyclin kinase inhibitor p40SIC1. Knapp, D., Bhoite, L., Stillman, D.J., Nasmyth, K. Mol. Cell. Biol. (1996) [Pubmed]
  8. SIC1 is ubiquitinated in vitro by a pathway that requires CDC4, CDC34, and cyclin/CDK activities. Verma, R., Feldman, R.M., Deshaies, R.J. Mol. Biol. Cell (1997) [Pubmed]
  9. Swi5 controls a novel wave of cyclin synthesis in late mitosis. Aerne, B.L., Johnson, A.L., Toyn, J.H., Johnston, L.H. Mol. Biol. Cell (1998) [Pubmed]
  10. Mutations in SID2, a novel gene in Saccharomyces cerevisiae, cause synthetic lethality with sic1 deletion and may cause a defect during S phase. Jacobson, M.D., Muñoz, C.X., Knox, K.S., Williams, B.E., Lu, L.L., Cross, F.R., Vallen, E.A. Genetics (2001) [Pubmed]
  11. Glucose inhibits meiotic DNA replication through SCFGrr1p-dependent destruction of Ime2p kinase. Purnapatre, K., Gray, M., Piccirillo, S., Honigberg, S.M. Mol. Cell. Biol. (2005) [Pubmed]
  12. Mutations of the CK2 phosphorylation site of Sic1 affect cell size and S-Cdk kinase activity in Saccharomyces cerevisiae. Coccetti, P., Rossi, R.L., Sternieri, F., Porro, D., Russo, G.L., di Fonzo, A., Magni, F., Vanoni, M., Alberghina, L. Mol. Microbiol. (2004) [Pubmed]
  13. Transferable domain in the G(1) cyclin Cln2 sufficient to switch degradation of Sic1 from the E3 ubiquitin ligase SCF(Cdc4) to SCF(Grr1). Berset, C., Griac, P., Tempel, R., La Rue, J., Wittenberg, C., Lanker, S. Mol. Cell. Biol. (2002) [Pubmed]
  14. Genetic and biochemical evaluation of the importance of Cdc6 in regulating mitotic exit. Archambault, V., Li, C.X., Tackett, A.J., Wasch, R., Chait, B.T., Rout, M.P., Cross, F.R. Mol. Biol. Cell (2003) [Pubmed]
  15. F-box proteins are receptors that recruit phosphorylated substrates to the SCF ubiquitin-ligase complex. Skowyra, D., Craig, K.L., Tyers, M., Elledge, S.J., Harper, J.W. Cell (1997) [Pubmed]
  16. Phosphorylation of sic1, a cyclin-dependent kinase (Cdk) inhibitor, by Cdk including Pho85 kinase is required for its prompt degradation. Nishizawa, M., Kawasumi, M., Fujino, M., Toh-e, A. Mol. Biol. Cell (1998) [Pubmed]
  17. Saccharomyces cerevisiae Ime2 phosphorylates Sic1 at multiple PXS/T sites but is insufficient to trigger Sic1 degradation. Sedgwick, C., Rawluk, M., Decesare, J., Raithatha, S., Wohlschlegel, J., Semchuk, P., Ellison, M., Yates, J., Stuart, D. Biochem. J. (2006) [Pubmed]
  18. APC(Cdc20) promotes exit from mitosis by destroying the anaphase inhibitor Pds1 and cyclin Clb5. Shirayama, M., Tóth, A., Gálová, M., Nasmyth, K. Nature (1999) [Pubmed]
  19. Cfi1 prevents premature exit from mitosis by anchoring Cdc14 phosphatase in the nucleolus. Visintin, R., Hwang, E.S., Amon, A. Nature (1999) [Pubmed]
  20. Hog1 mediates cell-cycle arrest in G1 phase by the dual targeting of Sic1. Escoté, X., Zapater, M., Clotet, J., Posas, F. Nat. Cell Biol. (2004) [Pubmed]
  21. End of the line: proteolytic degradation of cyclin-dependent kinase inhibitors. Sheaff, R.J., Roberts, J.M. Chem. Biol. (1996) [Pubmed]
  22. Two yeast forkhead genes regulate the cell cycle and pseudohyphal growth. Zhu, G., Spellman, P.T., Volpe, T., Brown, P.O., Botstein, D., Davis, T.N., Futcher, B. Nature (2000) [Pubmed]
  23. The Cdk-activating kinase Cak1p promotes meiotic S phase through Ime2p. Schindler, K., Benjamin, K.R., Martin, A., Boglioli, A., Herskowitz, I., Winter, E. Mol. Cell. Biol. (2003) [Pubmed]
  24. Cdc4, a protein required for the onset of S phase, serves an essential function during G(2)/M transition in Saccharomyces cerevisiae. Goh, P.Y., Surana, U. Mol. Cell. Biol. (1999) [Pubmed]
  25. Sic1 is phosphorylated by CK2 on Ser201 in budding yeast cells. Coccetti, P., Zinzalla, V., Tedeschi, G., Russo, G.L., Fantinato, S., Marin, O., Pinna, L.A., Vanoni, M., Alberghina, L. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
 
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