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

TY - JOUR

T1 - RPS6KA2, a putative tumour suppressor gene at 6q27 in sporadic epithelial ovarian cancer

AU - Bignone, P A

AU - Lee, K Y

AU - Liu, Y

AU - Emilion, G

AU - Finch, J

AU - Soosay, A E R

AU - Charnock, F M L

AU - Beck, S

AU - Dunham, I

AU - Mungall, A J

AU - Ganesan, T S

PY - 2007/2/1

Y1 - 2007/2/1

N2 - 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.

AB - 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.

KW - Adenocarcinoma, Clear Cell

KW - Adenocarcinoma, Mucinous

KW - Amino Acid Sequence

KW - Apoptosis

KW - Carcinoma, Endometrioid

KW - Cell Cycle

KW - Cell Proliferation

KW - Chromosome Deletion

KW - Chromosome Mapping

KW - Chromosomes, Human, Pair 6

KW - Cystadenocarcinoma, Serous

KW - DNA Methylation

KW - DNA, Neoplasm

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Genes, Tumor Suppressor

KW - Humans

KW - Immunoprecipitation

KW - Loss of Heterozygosity

KW - MAP Kinase Signaling System

KW - Mitogen-Activated Protein Kinases

KW - Molecular Sequence Data

KW - Neoplasms, Glandular and Epithelial

KW - Ovarian Neoplasms

KW - Polymerase Chain Reaction

KW - Polymorphism, Single-Stranded Conformational

KW - RNA Interference

KW - Ribosomal Protein S6 Kinases, 90-kDa

KW - Sequence Homology, Amino Acid

KW - Transfection

KW - Tumor Cells, Cultured

U2 - 10.1038/sj.onc.1209827

DO - 10.1038/sj.onc.1209827

M3 - Journal article

C2 - 16878154

SN - 0950-9232

VL - 26

SP - 683

EP - 700

JO - Oncogene

JF - Oncogene

IS - 5

ER -