Heterogeneous nuclear ribonucleoprotein H blocks MST2-mediated apoptosis in cancer cells by regulating A-Raf transcription.
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.
Department of Head and Neck Research, Ludwig-Maximilians-Universität München, D-81377 Munich, Germany.
Jens
J
Rauch
Eric
E
O'Neill
Brigitte
B
Mack
Christoph
C
Matthias
Markus
M
Munz
Walter
W
Kolch
Olivier
O
Gires
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006367:HeLa Cells; D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D048491:Proto-Oncogene Proteins A-raf / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D000090742:Serine-Threonine Kinase 3; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D000099317:Hippo Kinases
D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H; D017346:Protein Serine-Threonine Kinases; D048491:Proto-Oncogene Proteins A-raf; D034741:RNA, Small Interfering; D000090742:Serine-Threonine Kinase 3; C097835:STK3 protein, human; D000099317:Hippo Kinases