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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma, Clear Cell / genetics
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Adenocarcinoma, Clear Cell / metabolism
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Adenocarcinoma, Clear Cell / pathology
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Adenocarcinoma, Mucinous / genetics
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Adenocarcinoma, Mucinous / metabolism
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Adenocarcinoma, Mucinous / pathology
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Amino Acid Sequence
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Apoptosis
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Carcinoma, Endometrioid / genetics
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Carcinoma, Endometrioid / metabolism
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Carcinoma, Endometrioid / pathology
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Cell Cycle
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Cell Proliferation
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Chromosome Deletion
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Chromosome Mapping
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Chromosomes, Human, Pair 6 / genetics*
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Cystadenocarcinoma, Serous / genetics
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Cystadenocarcinoma, Serous / metabolism
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Cystadenocarcinoma, Serous / pathology
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DNA Methylation
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DNA, Neoplasm / genetics
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DNA, Neoplasm / metabolism
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Female
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Gene Expression Regulation, Neoplastic
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Genes, Tumor Suppressor / physiology*
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Humans
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Immunoprecipitation
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Loss of Heterozygosity
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MAP Kinase Signaling System / genetics
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Mitogen-Activated Protein Kinases
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Molecular Sequence Data
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Neoplasms, Glandular and Epithelial / genetics*
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Neoplasms, Glandular and Epithelial / metabolism
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Neoplasms, Glandular and Epithelial / pathology
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Ovarian Neoplasms / genetics*
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Ovarian Neoplasms / metabolism
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Ovarian Neoplasms / pathology
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Polymerase Chain Reaction
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Polymorphism, Single-Stranded Conformational
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RNA Interference
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Ribosomal Protein S6 Kinases, 90-kDa / genetics
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Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
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Sequence Homology, Amino Acid
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Transfection
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Tumor Cells, Cultured
Substances
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DNA, Neoplasm
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Ribosomal Protein S6 Kinases, 90-kDa
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Mitogen-Activated Protein Kinases