Heterogeneous nuclear ribonucleoprotein H blocks MST2-mediated apoptosis in cancer cells by regulating A-Raf transcription.

Abstract

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.

• Authors: Jens Rauch, Eric O'Neill, Brigitte Mack, Christoph Matthias, Markus Munz, Walter Kolch, Olivier Gires
• Journal: Cancer research (Cancer Res) Vol. 70 Issue 4 Pg. 1679-88 (Feb 15 2010) ISSN: 1538-7445 [Electronic] United States
• PMID: 20145135 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Heterogeneous-Nuclear Ribonucleoprotein Group F-H
• RNA, Small Interfering
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins A-raf
• STK3 protein, human
• Serine-Threonine Kinase 3

Topics

• Apoptosis (drug effects, genetics)
• Cells, Cultured
• Gene Expression Regulation, Neoplastic (drug effects)
• HCT116 Cells
• HeLa Cells
• Heterogeneous-Nuclear Ribonucleoprotein Group F-H (antagonists & inhibitors, genetics, physiology)
• Humans
• Models, Biological
• Neoplasms (genetics, metabolism, pathology)
• Protein Binding (drug effects)
• Protein Serine-Threonine Kinases (genetics, metabolism, physiology)
• Proto-Oncogene Proteins A-raf (genetics, metabolism)
• RNA, Small Interfering (pharmacology)
• Serine-Threonine Kinase 3
• Signal Transduction (drug effects, genetics)
• Transcription, Genetic (drug effects)