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Gene Review

CKS1B  -  CDC28 protein kinase regulatory subunit 1B

Homo sapiens

Synonyms: CKS-1, CKS1, Cyclin-dependent kinases regulatory subunit 1, PNAS-143, PNAS-16, ...
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Disease relevance of CKS1B

  • Cks1 could play an important role in gastric carcinoma progression and would be a novel target for the treatment of gastric carcinomas as well as a strong prognostic marker [1].
  • Amplification and overexpression of CKS1B at chromosome band 1q21 is associated with reduced levels of p27Kip1 and an aggressive clinical course in multiple myeloma [2].
  • In the present study, we examined Cks1 expression and its correlation with p27 in oral squamous cell carcinoma (OSCC) derived from tongue and gingiva [3].
  • When analysis was restricted solely to acute lymphoblastic leukemia (ALL) this correlation was still found and ckshs1 and ckshs2 were significantly more expressed in T-cell ALL than in B-cell-lineage ALL [4].
  • Here we show high expression of Cks1 in non-small cell lung cancers (NSCLCs) using Western blotting and quantitative real-time RT-PCR [5].

High impact information on CKS1B

  • The phosphorylated Thr187 side chain of p27(Kip1) is recognized by a Cks1 phosphate binding site, whereas the side chain of an invariant Glu185 inserts into the interface between Skp2 and Cks1, interacting with both [6].
  • Here we show that the missing factor is CDK subunit 1 (Cks1), which belongs to the highly conserved Suc1/Cks family of proteins that bind to some CDKs and phosphorylated proteins and are essential for cell-cycle progression [7].
  • Particularly, we did not detect the down-regulation of Skp2 and Cks1, two proteins involved in the nuclear ubiquitin-dependent p27Kip1 removal [8].
  • Moreover, we inhibited Cks1 expression by small interference RNA (siRNA) in OSCC [3].
  • Cks1 siRNA transfection induced p27 accumulation and inhibited the growth of OSCC cells [3].

Chemical compound and disease context of CKS1B


Biological context of CKS1B


Anatomical context of CKS1B


Associations of CKS1B with chemical compounds

  • A conservative change from Asp to Glu at position 331 of Skp2 does not affect Skp2-Cks1 interaction [15].
  • Activation of Ubiquitin Ligase SCF(Skp2) by Cks1: Insights from Hydrogen Exchange Mass Spectrometry [16].
  • The expression of Cks1 was also examined by immunohistochemistry using formalin-fixed, paraffin-embedded tissue sections from the same patients [17].
  • Overexpression of Cks1 was associated with loss of tumor differentiation, young age, lack of expression of estrogen receptors and of progesterone receptors, and decreased disease-free (P = 0.0007) and overall (P = 0.041) survival [18].
  • In addition, Cks1 and Skp2 expression were increased by estradiol in estrogen-dependent cell lines but were down-regulated by tamoxifen [18].

Physical interactions of CKS1B

  • Here we show that the Skp2-binding site of Cks1 is located on a region including the alpha2- and alpha1-helices and their immediate vicinity, well separated from the other two binding sites [10].
  • Previous studies have shown that the cyclin-dependent kinase (Cdk) inhibitor p27(Kip1) is targeted for degradation by an SCF(Skp2) ubiquitin ligase complex and that this process requires Cks1, a member of the highly conserved Suc1/Cks family of cell cycle regulatory proteins [10].

Regulatory relationships of CKS1B


Other interactions of CKS1B

  • Mutation of Asp-331 to Ala disrupts the interaction between Skp2 and Cks1 [15].
  • The mechanisms by which Skp2 recognizes Cks1 to ubiquitylate p27 remain obscure [15].
  • In particular, over-expression of CKS1B, which maps to an amplicon at 1q21 in myeloma and regulates SCF(Skp2)-mediated ubquitination and proteolysis of the cyclin dependent kinase inhibitor p27Kip1 was significantly over-expressed in patients with poor survival [2].
  • The prevalence and prognostic relevance of recurrent gains of CKS1B (cyclin kinase subunit 1B) gene at chromosome 1q21 region was investigated by interphase fluorescence in situ hybridisation in a cohort of 99 multiple myeloma (MM) patients treated with intensive chemotherapy followed by autologous stem cell transplantation [13].
  • CKS1B amplification (3-8 CKS1B signals) was detected in 31of 99 (31%) patients and was associated with deletions of p53 (P = 0.003) and 13q (P = 0.039) but not with translocation t(11;14) or t(4;14) [13].

Analytical, diagnostic and therapeutic context of CKS1B


  1. Cyclin-dependent kinase 1 gene expression is associated with poor prognosis in gastric carcinoma. Masuda, T.A., Inoue, H., Nishida, K., Sonoda, H., Yoshikawa, Y., Kakeji, Y., Utsunomiya, T., Mori, M. Clin. Cancer Res. (2003) [Pubmed]
  2. Amplification and overexpression of CKS1B at chromosome band 1q21 is associated with reduced levels of p27Kip1 and an aggressive clinical course in multiple myeloma. Shaughnessy, J. Hematology (2005) [Pubmed]
  3. Role of Cks1 overexpression in oral squamous cell carcinomas: cooperation with Skp2 in promoting p27 degradation. Kitajima, S., Kudo, Y., Ogawa, I., Bashir, T., Kitagawa, M., Miyauchi, M., Pagano, M., Takata, T. Am. J. Pathol. (2004) [Pubmed]
  4. ckshs expression is linked to cell proliferation in normal and malignant human lymphoid cells. Urbanowicz-Kachnowicz, I., Baghdassarian, N., Nakache, C., Gracia, D., Mekki, Y., Bryon, P.A., Ffrench, M. Int. J. Cancer (1999) [Pubmed]
  5. High expression of Cks1 in human non-small cell lung carcinomas. Inui, N., Kitagawa, K., Miwa, S., Hattori, T., Chida, K., Nakamura, H., Kitagawa, M. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  6. Structural basis of the Cks1-dependent recognition of p27(Kip1) by the SCF(Skp2) ubiquitin ligase. Hao, B., Zheng, N., Schulman, B.A., Wu, G., Miller, J.J., Pagano, M., Pavletich, N.P. Mol. Cell (2005) [Pubmed]
  7. The cell-cycle regulatory protein Cks1 is required for SCF(Skp2)-mediated ubiquitinylation of p27. Ganoth, D., Bornstein, G., Ko, T.K., Larsen, B., Tyers, M., Pagano, M., Hershko, A. Nat. Cell Biol. (2001) [Pubmed]
  8. Retinoic acid induces p27Kip1 nuclear accumulation by modulating its phosphorylation. Borriello, A., Cucciolla, V., Criscuolo, M., Indaco, S., Oliva, A., Giovane, A., Bencivenga, D., Iolascon, A., Zappia, V., Della Ragione, F. Cancer Res. (2006) [Pubmed]
  9. The prognostic impact of the ubiquitin ligase subunits Skp2 and Cks1 in colorectal carcinoma. Shapira, M., Ben-Izhak, O., Linn, S., Futerman, B., Minkov, I., Hershko, D.D. Cancer (2005) [Pubmed]
  10. Three different binding sites of Cks1 are required for p27-ubiquitin ligation. Sitry, D., Seeliger, M.A., Ko, T.K., Ganoth, D., Breward, S.E., Itzhaki, L.S., Pagano, M., Hershko, A. J. Biol. Chem. (2002) [Pubmed]
  11. Using genomics to identify high-risk myeloma after autologous stem cell transplantation. Shaughnessy, J.D., Barlogie, B. Biol. Blood Marrow Transplant. (2006) [Pubmed]
  12. Significant increase of CKS1B amplification from monoclonal gammopathy of undetermined significance to multiple myeloma and plasma cell leukaemia as demonstrated by interphase fluorescence in situ hybridisation. Chang, H., Yeung, J., Xu, W., Ning, Y., Patterson, B. Br. J. Haematol. (2006) [Pubmed]
  13. Multiple myeloma patients with CKS1B gene amplification have a shorter progression-free survival post-autologous stem cell transplantation. Chang, H., Qi, X., Trieu, Y., Xu, W., Reader, J.C., Ning, Y., Reece, D. Br. J. Haematol. (2006) [Pubmed]
  14. Retinoic acid stabilizes p27Kip1 in EBV-immortalized lymphoblastoid B cell lines through enhanced proteasome-dependent degradation of the p45Skp2 and Cks1 proteins. Zancai, P., Dal Col, J., Piccinin, S., Guidoboni, M., Cariati, R., Rizzo, S., Boiocchi, M., Maestro, R., Dolcetti, R. Oncogene (2005) [Pubmed]
  15. A negatively charged amino acid in Skp2 is required for Skp2-Cks1 interaction and ubiquitination of p27Kip1. Wang, W., Ungermannova, D., Chen, L., Liu, X. J. Biol. Chem. (2003) [Pubmed]
  16. Activation of Ubiquitin Ligase SCF(Skp2) by Cks1: Insights from Hydrogen Exchange Mass Spectrometry. Yao, Z.P., Zhou, M., Kelly, S.E., Seeliger, M.A., Robinson, C.V., Itzhaki, L.S. J. Mol. Biol. (2006) [Pubmed]
  17. Alterations in the expression of the cell cycle regulatory protein cyclin kinase subunit 1 in colorectal carcinoma. Shapira, M., Ben-Izhak, O., Bishara, B., Futerman, B., Minkov, I., Krausz, M.M., Pagano, M., Hershko, D.D. Cancer (2004) [Pubmed]
  18. The expression of the ubiquitin ligase subunit Cks1 in human breast cancer. Slotky, M., Shapira, M., Ben-Izhak, O., Linn, S., Futerman, B., Tsalic, M., Hershko, D.D. Breast Cancer Res. (2005) [Pubmed]
  19. RNA silencing of Cks1 induced G2/M arrest and apoptosis in human lung cancer cells. Tsai, Y.S., Chang, H.C., Chuang, L.Y., Hung, W.C. IUBMB Life (2005) [Pubmed]
  20. Prognostic value of chromosome 1q21 gain by fluorescent in situ hybridization and increase CKS1B expression in myeloma. Fonseca, R., Van Wier, S.A., Chng, W.J., Ketterling, R., Lacy, M.Q., Dispenzieri, A., Bergsagel, P.L., Rajkumar, S.V., Greipp, P.R., Litzow, M.R., Price-Troska, T., Henderson, K.J., Ahmann, G.J., Gertz, M.A. Leukemia (2006) [Pubmed]
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