Role of p90 ribosomal S6 kinase 4 (RSK4), a putative tumor suppressor gene, in breast cancer development

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RSK4, an X-linked gene, has recently been shown to be a component of the p53 tumor suppressor pathway and signals downstream of MAPK/ERK pathway. The p90 ribosomal S6 kinases (RSKs) are intercellular serine/threonine kinases and act on a diverse array of substrates including transcription factors, which play prominent roles in cell proliferation and survival. In strong contrast to RSK1-3, inhibition of RSK4 confers resistance to p53-dependent proliferation arrest suggesting that RSK4 may likely to be a tumor suppressor gene. The main purpose of this study is to explore the biological and pathological significance of RSK4 and how RSK4 selectively activates substrates, which may mediate its tumor suppressive effects. We have recently shown that mammary tumors of MMTV-c-myc transgenic or MMTV-c-myc/MT-tgf-α double transgenic mice expressed 20-30 fold higher RSK4 compared to the lactating or normal mammary glands. Transient transfection with pMT2-HA-RSK4 (RSK4) plasmid in HeLa cells showed reduced viability and increased fraction of sub-G1 and G1 cell cycle arrest after treatment with 5’-deoxy-5-fluorouridine.RSK4 transfected HeLa cells showed increased expression of three tumor suppressor genes, p21, Lucine zipper down regulated in cancer (LDOC1) and retinoblatoma associated 46kDa protein (RbAp46), while decreased expression of cyclin D1. LDOC1 and RbAp46 have been shown to suppress tumor growth and induce apoptosis. These data imply that RSK4 induced tumor suppressors, p21, LDOC1 and RbAp46, may play a role in RSK4 mediated growth arrest and increased chemosensitivity to chemotherapeutic drugs. In conclusion, our data indicate that the X-linked gene-RSK4 may have anti-proliferative and pro-apoptotic effects.