Oncogene database

1163

CKS1B

CDC28 protein kinase regulatory subunit 1B;CKS1B;CDC28 protein kinase regulatory subunit 1B

CDC2-associated protein CKS1|CDC28 protein kinase 1|CDC28 protein kinase 1B|CKS-1|NB4 apoptosis/differentiation related protein|PNAS-143|cell division control protein CKS1|cyclin-dependent kinases regulatory subunit 1

1q21.2

protein-coding

Cks1 is a member of the cyclin-dependent kinase subunit family. These proteins are essential components of cyclin/cyclin-dependent kinase (cdk) complexes contributing to cell cycle control in ALL eukaryotes. Cks1 protein is found overexpressed in a number of tumors. expression of Cks1 mRNA starts in late G1 reaching a peak in S/G2-phases of the cell cycle. We find that this expression pattern depends on transcriptional regulation and is controlled by a combination of a cell cycle-dependent element (CDE) together with a cell cycle genes homology region (CHR) in the Cks1 promoter. Furthermore, we observe Cks1 mRNA and protein to be downregulated after induced expression of the tumor suppressor p53. This repression is due to p53 downregulating transcription from the Cks1 promoter. p53-dependent repression is seen in a dose-dependent manner and in several cell types of different origin. In contrast to p53, its homologues p63 and p73 do not significantly repress transcription from the Cks1 promoter. The Cks1 promoter does not contain a p53 binding site. For some promoters the CCAAT box-binding transcription factor NF-Y had been implicated in p53-dependent repression. NF-Y is the main activator for Cks1 transcription but does not influence p53-dependent repression from the Cks1 promoter. Generally, the observation that the potential oncogene Cks1 is downregulated by the tumor suppressor p53 corresponds well with the idea that p53 employs multiple ways in order to halt the cell cycle.

Gain of chromosome 1q is a common event in many kinds of carcinomas. The Cks1 gene, located at 1q21, is required for p27 ubiquitination by the SCF(skp2) ubiquitinating machinery. In the present study, we found that Cks1 gene amplification was highly correlated with protein overexpression. Statistical analysis showed that amplification and overexpression of Cks1 were strongly associated with lymph node metastasis and poor prognosis. At the molecular level, knockdown of Cks1 expression by RNA interference inhibited the growth of MDA-MB-231 cells, damaged cell migration and invasion ability. Knockdown of Cks1 expression promoted apoptosis of breast cancer cells and a wobble mutant of Cks1 that was resistant to Cks1 siRNA can rescue this effect. Overexpression of Cks1 inhibited the apoptosis of breast cancer cells through the MEK-Erk pathway. These data suggest that Cks1 is an oncogene in the 1q21 amplicon and plays an important role for breast cancer development.

BACKGROUND: Through data mining the Stanford Microarray Database, the CKS1B transcript was found to be frequently upregulated in hepatocellular carcinomas (HCCs) with low alpha-fetal protein (AFP) expression. Together with SKP2, CKS1B is known to implicate p27(Kip1) protein turnover promoting cell-cycle progression. METHODS: CKS1B, p27(Kip1), and SKP2 were immunostained in 75 HCCs and correlated with clinicopathological features, local recurrence-free survival (LRFS), and overall survival (OS). Silencing of CKS1B and SKP2 with interference short-hairpin RNA (shRNA) was performed in SK-Hep1 and Hep-3B cell lines. RESULTS: Immunohistochemically, increased CKS1B and SKP2, and attenuated p27(Kip1) were ALL associated with tumor multiplicity (P < 0.05) and increasing American Joint Committee on cancer (AJCC) stage (P < 0.05). Overexpression of CKS1B significantly correlated with advanced Okuda stages (P = 0.048) and SKP2 overexpression (P = 0.047). Neither CKS1B nor SKP2 was inversely related to p27(Kip1), which was reinforced by no alteration in p27(Kip1) abundance in HCC-derived cells with CKS1B or SKP2 silencing. Both CKS1B overexpression (P = 0.0011 and P = 0.0017) and p27(Kip1) attenuation (P = 0.0079 and P = 0.0085) were predictive of OS and LRFS, respectively, while SKP2 overexpression was associated with worse OS alone (P = 0.0043). Combined assessment of CKS1B and p27(Kip1) was able to robustly distinguish three prognostically different groups (P < 0.0001). In multivariate comparison, CKS1B overexpression represented the strongest independent adverse prognosticator [OS, P = 0.0235, hazard ratio (HR): 4.193; LRFS, P = 0.0204, HR: 4.262], followed by p27(Kip1) attenuation (OS, P = 0.0320, HR: 2.553; LRFS, P = 0.0262, HR: 2.533). CONCLUSIONS: CKS1B protein overexpression in HCCs is implicated in clinical aggressiveness but not in p27(Kip1) turnover, implying presence of p27(Kip1)-independent oncogenic attributes. The combined assessment of CKS1B and p27(Kip1) immunoexpressions effectively risk-stratifies HCCs with different prognoses, which may aid in the management of this deadly malignancy.