RPS6KA2, a putative tumour suppressor gene at 6q27 in sporadic epithelial ovarian cancer

Abstract

We had previously defined by allele loss studies a minimal region at 6q27 (between D6S264 and D6S297) to contain a putative tumour suppressor gene. The p90 ribosomal S6 kinase-3 gene (p90 Rsk-3, RPS6KA2) maps in this interval. It is a serine-threonine kinase that signals downstream of the mitogen-activated protein kinase pathway. It is expressed in normal ovarian epithelium, whereas reduced or absent in tumours or cell lines. We show that RPS6KA2 is monoallelically expressed in the ovary suggesting that loss of a single expressed allele is sufficient to cause complete loss of expression in cancer cells. Further, we have identified two new isoforms of RPS6KA2 with an alternative start codon. Homozygous deletions were identified within the RPS6KA2 gene in two cell lines. Re-expression of RPS6KA2 in ovarian cancer cell lines suppressed colony formation. In UCI101 cells, the expression of RPS6KA2 reduced proliferation, caused G1 arrest, increased apoptosis, reduced levels of phosphorylated extracellular signal-regulated kinase and altered other cell cycle proteins. In contrast, small interfering RNA against RPS6KA2 showed the opposite effect in 41M cells. The above results suggest that RPS6KA2 is a putative tumour suppressor gene to explain allele loss at 6q27.

A Minimal DNA Methylation Signature in Oral Tongue Squamous Cell Carcinoma Links Altered Methylation with Tumor Attributes

“…Several of those are shown in the past to have a role in cancer. For example, TSPAN7, a tetraspanin family member upregulated in multiple myeloma patients (45) in human epithelial malignancies (46), FUT3 in gastric cancer (47), SLC9A9, overexpressed in most cancers (http://www.proteinatlas.org/ ENSG00000181804-SLC9A9/cancer), NPAS3, a neuronal PAS transcriptional factor family member as a tumor suppressor in astrocyomal progression (48), RPS6KA2, a ribosomal kinase and as a putative tumor suppressor in sporadic epithelial ovarian cancer (49) and a modifier of the EGFR signaling pathway in pancreatic cancer (50), and MAP3K8 as a proto-oncogene that plays a role in lung (51), prostrate (52), and colorectal (53) cancers.…”

Two p90 Ribosomal S6 Kinase Isoforms Are Involved in the Regulation of Mitotic and Meiotic Arrest in Artemia

“…Rsk1 and Rsk2 may also promote G 1 phase progression by controlling the activity of p27 kip1 , a cyclin-dependent kinase 2 inhibitor (39). However, Rsk3 was recently shown to act as a tumor suppressor in ovarian cancer (40), and several lines of evidence suggest that Rsk4 negatively regulates cell proliferation (41). The current study shows that RSK isoforms also have distinct functions in Artemia; ArRsk1 regulates meiosis, whereas Ar-Rsk2 regulates mitosis.…”

Anti-proliferative and pro-apoptotic actions of a novel human and mouse ovarian tumor-associated gene OTAG-12: downregulation, alternative splicing and drug sensitization

“…Others have reported a similar inability for overexpression of wild-type gene and for establishing cell lines for tumor suppressors such as OVCA1 (Bruening et al, 1999) and RPS6KA2 (Bignone et al, 2007) in OC cells. This led us to generate DOXcontrolled strategies that resulted in securing a workable system with HEK293 cells and providing an experimental tool to manipulate hOTAG-12b expression and explore mechanistic issues.…”

“…Tumor suppressor genes have key roles in cell growth, proliferation, apoptosis and tumor development (Bruening et al, 1999;Luo et al, 2003;Bignone et al, 2007;Bast et al, 2009). Sixteen candidate tumor suppressor genes have been studied in OC (Bast Jr et al, 2009).…”