title: Identification of a c-Jun N-terminal kinase-2-dependent signal amplification cascade that regulates c-Myc levels in ras transformation.
abstract: 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.
authors.affiliation: Apoptosis Department and Centre for Genotoxic Stress Research, Institute of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark.
authors.forename: D P
authors.initials: DP
authors.lastname: Mathiasen
authors.forename: C
authors.initials: C
authors.lastname: Egebjerg
authors.forename: S H
authors.initials: SH
authors.lastname: Andersen
authors.forename: B
authors.initials: B
authors.lastname: Rafn
authors.forename: P
authors.initials: P
authors.lastname: Puustinen
authors.forename: A
authors.initials: A
authors.lastname: Khanna
authors.forename: M
authors.initials: M
authors.lastname: Daugaard
authors.forename: E
authors.initials: E
authors.lastname: Valo
authors.forename: S
authors.initials: S
authors.lastname: Tuomela
authors.forename: T
authors.initials: T
authors.lastname: Bøttzauw
authors.forename: C F
authors.initials: CF
authors.lastname: Nielsen
authors.forename: B M
authors.initials: BM
authors.lastname: Willumsen
authors.forename: S
authors.initials: S
authors.lastname: Hautaniemi
authors.forename: R
authors.initials: R
authors.lastname: Lahesmaa
authors.forename: J
authors.initials: J
authors.lastname: Westermarck
authors.forename: M
authors.initials: M
authors.lastname: Jäättelä
authors.forename: T
authors.initials: T
authors.lastname: Kallunki
mesh_terms: D051698:Activating Transcription Factor 2 / Q000378:metabolism; D051700:Activating Transcription Factor 3 / Q000096:biosynthesis; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D011905:Genes, ras / Q000502:physiology*; D020935:MAP Kinase Signaling System; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism*; D054648:Protein Phosphatase 2 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D051698:Activating Transcription Factor 2; D051700:Activating Transcription Factor 3; C497106:Atf2 protein, mouse; C103002:Atf3 protein, mouse; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D048056:Mitogen-Activated Protein Kinase 9; D054648:Protein Phosphatase 2; D018631:ras Proteins