Identification of a c-Jun N-terminal kinase-2-dependent signal amplification cascade that regulates c-Myc levels in ras transformation

• Published in: Oncogene Vol. 31; no. 3; p. 390
• Main Authors: Mathiasen, D.P, Egebjerg, C, Andersen, S.H, Rafn, B, Puustinen, P, Khanna, A, Daugaard, M, Valo, E, Tuomela, S, Bottzauw, T, Nielsen, C.F, Willumsen, B.M, Hautaniemi, S, Lahesmaa, R, Westermarck, J, Jaattela, M, Kallunki, T
• Format: Journal Article
• Language: English
• Published: Nature Publishing Group 19-01-2012
• Subjects: Cellular signal transduction; Genetic aspects; Genetic transformation; Oncogenes; Properties; Transcription factors; United States
• ISSN: 0950-9232
• DOI: 10.1038/onc.2011.230;

Ras is one of the most frequently activated oncogenes in cancer. Two mitogen-activated protein kinases (MAPKs) are important for ras transformation: extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase 2 (JNK2). Here we present a downstream signal amplification cascade that is critical for ras transformation in murine embryonic fibroblasts. This cascade is coordinated by ERK and JNK2 MAPKs, whose Ras-mediated activation leads to the enhanced levels of three oncogenic transcription factors, namely, c-Myc, activating transcription factor 2 (ATF2) and ATF3, all of which are essential for ras transformation. Previous studies show that ERK-mediated serine 62 phosphorylation protects c-Myc from proteasomal degradation. ERK is, however, not alone sufficient to stabilize c-Myc but requires the cooperation of cancerous inhibitor of protein phosphatase 2A (CIP2A), an oncogene that counteracts protein phosphatase 2A-mediated dephosphorylation of c-Myc. Here we show that JNK2 regulates Cip2a transcription via ATF2. ATF2 and c-Myc cooperate to activate the transcription of ATF3. Remarkably, not only ectopic JNK2, but also ectopic ATF2, CIP2A, c-Myc and ATF3 are sufficient to rescue the defective ras transformation of JNK2-deficient cells. Thus, these data identify the key signal converging point of JNK2 and ERK pathways and underline the central role of CIP2A in ras transformation. Oncogene (2012) 31, 390-401; doi: 10.1038/onc.2011.230; published online 27 June 2011 Keywords: JNK knockout; CIP2A; ATF3; c-Myc; Ras transformation