1. ¹Cancer Research UK, Molecular Oncology Laboratories, Ovarian Cancer Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, UK
2. ²The Sanger Centre, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK

Correspondence: Professor TS Ganesan, Cancer Research UK, Molecular Oncology Laboratories, Ovarian Cancer Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK. E-mail:ganesan@cancer.org.uk

³These authors contributed equally to this work.

⁴Current address: Cancer Institute and Institute of Molecular Medicine, Amrita Institute of Medical Sciences, Elamakkara PO, Cochin 682026, India. E-mail: tsganesan@aims.amrita.edu

Received 23 February 2006; Revised 25 May 2006; Accepted 8 June 2006; Published online 31 July 2006.

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.