Heterogeneous Nuclear Ribonucleoprotein H Blocks MST2-Mediated Apoptosis in Cancer Cells by Regulating a-raf Transcription

Rauch, J., O'Neill, E., Mackinnon, B., Matthias, C., Munz, M., Kolch, W. and Gires, O. (2010) Heterogeneous Nuclear Ribonucleoprotein H Blocks MST2-Mediated Apoptosis in Cancer Cells by Regulating a-raf Transcription. Cancer Research, 70(4), pp. 1679-1688. (doi: 10.1158/0008-5472.CAN-09-2740)

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. Cancer Res; 70(4); 1679-88. (C) 2010 AACR

• Item Type: Articles
• Keywords: ACTIVATION Apoptosis B-RAF BCL-X CANCER CELL-DEATH CELLS CYCLE EXIT DEATH DROSOPHILA EXPRESSION FAMILY GENE GREEN HEAD HNRNP H IN-VIVO KINASE LEVEL MECHANISM NUCLEIC-ACIDS PATHWAY PROMOTES APOPTOSIS PROTEIN SEQUESTRATION SIGNALING PATHWAYS TISSUE TUMOR-CELLS TUMOR-SUPPRESSOR
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Rauch, Dr Jens and Mackinnon, Dr Bruce and O'Neill, Mr Eric
• Authors: Rauch, J., O'Neill, E., Mackinnon, B., Matthias, C., Munz, M., Kolch, W., and Gires, O.
• College/School: College of Medical Veterinary and Life Sciences
• Journal Name: Cancer Research
• ISSN: 0008-5472