CKS1B

Function

The CKS1B protein binds to the catalytic subunit of the cyclin-dependent kinases and is essential for their biological function. The CKS1B mRNA is found to be expressed in different patterns through the cell cycle in HeLa cells, which reflects a specialized role for the encoded protein.

CKS1B and CKS2 proteins have demonstrated principal roles in cell cycle regulation. Defined originally as suppressors of mutations in both fission and budding yeast Cdk1 genes, Cks molecules interact with Cdk1, Cdk2 and Cdk3. These Cdk-dependent enzyme complexes in cell cycle regulation frequently consist of Cdk molecules bound to a catalytic Cdk subunit, i.e. Cks and a regulatory cyclin subunit, such as a G1 cyclin, controlling Cdk function by directing cyclin-cdk complex activity toward specific and significant substrates. Malfunctions of cdk-dependent associations lead to defects into the entry of mitosis for cells.

Cks1 in the Cdk-independent pathway involves the recognition of substrates p27Kip1 and p21cip1 by directly associating with E3 SCFSkp2 when stimulated by certain mitogenic signals, such as TGF-β.

Clinical significance

Cks1-depleted breast cancer cells not only exhibit slowed G(1) progression, but also accumulate in G(2)-M due to blocked mitotic entry. Cdk1 expression, which is crucial for M phase entry, is drastically diminished by Cks1 depletion, and that restoration of cdk1 reduces G(2)-M accumulation in Cks1-depleted cells.

Interactions

CKS1B has been shown to interact with SKP2 and CDKN1B.

References

References

1. (Dec 1990). "Human cDNAs encoding homologs of the small p34Cdc28/Cdc2-associated protein of Saccharomyces cerevisiae and Schizosaccharomyces pombe". Genes Dev.
2. "Entrez Gene: CKS1B CDC28 protein kinase regulatory subunit 1B".
3. Harper, J.W. 2001. Protein destruction: Adapting roles for Cks proteins. Cur Biol. 11: R431–R435
4. Xu, K., Belunis, C., et al. 2003. Protein-protein interactions involved in the recognition of p27 by E3 ubiquitin ligase. Biochem J. 371: 957–964.
5. (December 2007). "Cks1 regulates cdk1 expression: a novel role during mitotic entry in breast cancer cells". Cancer Res..
6. (August 2003). "A negatively charged amino acid in Skp2 is required for Skp2-Cks1 interaction and ubiquitination of p27Kip1". J. Biol. Chem..
7. (November 2002). "Three different binding sites of Cks1 are required for p27-ubiquitin ligation". J. Biol. Chem..
8. (March 2001). "The cell-cycle regulatory protein Cks1 is required for SCF(Skp2)-mediated ubiquitinylation of p27". Nat. Cell Biol..
9. (June 2008). "Dual-specificity phosphatase 1 ubiquitination in extracellular signal-regulated kinase-mediated control of growth in human hepatocellular carcinoma". Cancer Res..