The role of CKS proteins in cancer development

• Main Author: Luft, Christin
• Other Authors: Yu, Veronica ; Gil, Jesus
• Published: Imperial College London 2013
• Subjects: 610
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.572259

The mammalian CKS family consists of two highly conserved proteins, CKS1 and CKS2. Both are able to bind to cyclin dependent kinases 1 and 2 (CDK1 and CDK2) with high affinity and were suggested to modulate CDK activity and thus cell cycle control. CKS proteins have also been reported to facilitate the ubiquitination of cyclin A by the anaphase promoting complex (APC). Additionally CKS1 has been shown to have an important role in the recognition of the cyclin dependent kinase inhibitor p27Kip1 by the SCFSkp2 (Skp1-Cul1-F-box-protein) ubiquitin ligase. Elevated expression of both CKS proteins is often found in a variety of tumours and is correlated with poor prognosis. This might indicate an involvement of CKS proteins in the process of transformation from normal to cancer cells. Previously it was shown that down-regulation of CKS proteins in cancer derived cell lines results in a loss of their high proliferative capacity. I surmise, that a possible oncogenic effect of CKS proteins might be due to the deregulation of replication. To study the role of CKS proteins as oncogenes, different stages of cancer development were modelled in the human diploid fibroblast cell line, IMR90. Over-expression of CKS proteins was combined with defined genetic events known to be associated with transformation such as activation of telomerase (hTERT) and blockage of the p53 and RB pathways. Over-expression of CKS variants in IMR90 cells led to checkpoint activation and growth arrest reminiscent of oncogenic stress. Down-regulation of the checkpoint proteins p53 and RB however could alleviate the growth arrest and led to a slight growth advantage of the CKS over-expressing fibroblasts. Analyses to understand the molecular mechanisms behind the checkpoint activation in primary IMR90 were performed addressing, in particular, the involvement of an altered CDK activity.