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A-Raf belongs to the family of oncogenic Raf kinases that are involved in mitogenic signaling by activating the mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK pathway. Low kinase activity of A-Raf toward MEK suggested that A-Raf might have alternative functions. Here, we show that A-Raf prevents cancer cell apoptosis contingent on the expression of the heterogeneous nuclear ribonucleoprotein H (hnRNP H) splice factor, which is required for the correct transcription and expression of a-raf. Apoptosis was prevented by A-Raf through sequestration and inactivation of the proapoptotic MST2 kinase. Small interfering RNA-mediated knockdown of hnRNP H or A-Raf resulted in MST2-dependent apoptosis. In contrast, enforced expression of either hnRNP H or A-Raf partially counteracted apoptosis induced by etoposide. In vivo expression studies of colon specimens corroborated the overexpression of hnRNP H in malignant tissues and its correlation with A-Raf levels. Our findings define a novel mechanism that is usurped in tumor cells to escape naturally imposed apoptotic signals.

Original publication

DOI

10.1158/0008-5472.CAN-09-2740

Type

Journal article

Journal

Cancer Res

Publication Date

15/02/2010

Volume

70

Pages

1679 - 1688

Keywords

Apoptosis, Cells, Cultured, Gene Expression Regulation, Neoplastic, HCT116 Cells, HeLa Cells, Heterogeneous-Nuclear Ribonucleoprotein Group F-H, Humans, Models, Biological, Neoplasms, Protein Binding, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins A-raf, RNA, Small Interfering, Signal Transduction, Transcription, Genetic