Cks1: Structure, Emerging Roles and Implications in Multiple Cancers

Abstract

Deregulation of the cell cycle results in loss of normal control mechanisms that prevent aberrant cell proliferation and cancer progression. Regulation of the cell cycle is a highly complex process with many layers of control. One of these mechanisms involves timely degradation of CDK inhibitors (CKIs) like p27Kip1 by the ubiquitin proteasomal system (UPS). Cks1 is a 9 kDa protein which is frequently overexpressed in different tumor subtypes, and has pleiotropic roles in cell cycle progression, many of which remain to be fully characterized. One well characterized molecular role of Cks1 is that of an essential adaptor that regulates p27Kip1 abundance by facilitating its interaction with the SCF-Skp2 E3 ligase which appends ubiquitin to p27Kip1 and targets it for degradation through the UPS. In addition, emerging research has uncovered p27Kip1-independent roles of Cks1 which have provided crucial insights into how it may be involved in cancer progression. We review here the structural features of Cks1 and their functional implications, and also some recently identified Cks1 roles and their involvement in breast and other cancers.

Increased expression of Cks1 protein is associated with lymph node metastasis and poor prognosis in nasopharyngeal carcinoma

“…P27 Kip1 is degraded in the late G1 phase via the ubiquitin–proteasome pathway [17]. The Cks1 protein is a member of the highly conserved family of Cks/Suc1 proteins which interact with Cdks and participates in numerous cellular processes including cell proliferation, growth and survival [18, 19]. One of well established mechanisms of Cks1 modulating cell cycle is to bind with the C-terminal of Skp2 to degrade p27 Kip1 and to promote cell cycle progression from G1 to S phase [7, 8, 18].…”

The cyclin dependent kinase subunit Cks1 is required for infection‐associated development of the rice blast fungus Magnaporthe oryzae

“…This may further support the idea that cAMP/PKA signalling pathway might operate upstream of cell cycle control points (Saunders et al ., ). In addition, the roles of Cks1 in growth factor signalling pathways, including MAPK regulation, had been reported (Khattar and Thottassery, ). In this study, however, no physical interactions were detected between Cks1 and several components involved in MAPK signalling pathways and cell cycle control processes in Y2H assays, such as Pmk1 (MGG_09565), Mps1 (MGG_04943), Mst7 (MGG_00800), Cdc10 (MGG_06726), Cdc11 (MGG_03087) and Cdc12 (MGG_07466) (data not shown).…”

“…Previous studies in a variety of organisms have demonstrated that Cks1/Suc1 is required for modulating cell cycle control, maintaining cellular growth and transcriptional regulation (Hayles et al, 1986b;Hindley et al, 1987;Richardson et al, 1990;Tang and Reed, 1993;Patra and Dunphy, 1996;Khattar and Thottassery, 2013). In S. cerevisiae, disruption of CKS1 leads to cells defective in G 1 /S and G 2 /M phase transitions, as well as the ability to bud (Tang and Reed, 1993).…”

Cks1 proteasomal degradation is induced by inhibiting Hsp90-mediated chaperoning in cancer cells

“…Cks1 is an evolutionarily conserved 9 kDa protein first identified as a component of yeast cyclin-Cdk complexes, which has been implicated in cell cycle progression, transcriptional regulation, and growth-signaling pathways [1]. Importantly, in the past few years, several studies, including ours, have demonstrated that Cks1 is highly upregulated in tumors [2][3][4][5][6].…”

“…Given its pleiotropic roles in the expression of tumorigenic phenotypes, inhibition of Cks1 has been suggested as a potential anticancer strategy [1]. Importantly, the therapeutic promise of such an approach has been validated in a myc-induced transgenic lymphoma model [13].…”