Role of mitogen-activated protein kinase kinase 4 in cancer

Whitmarsh, Alan J.; Davis, Roger J.

doi:10.1038/sj.onc.1210410

Cited by 142 publications

(108 citation statements)

References 124 publications

(183 reference statements)

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“…This finding provides evidence that upregulation of Ras with JNK may be important for the development of certain types of human cancer. In mammalian cells and human cancer, the role of JNK signaling is complex and context dependent (Kennedy and Davis 2003;Weston and Davis 2007;Whitmarsh and Davis 2007;Wagner and Nebreda 2009). However, our experiments support previous evidence that JNK pathway activation can cooperate with oncogenic Ras in mammalian cell transformation (Nielsen et al 2007;Zhang et al 2007;Ke et al 2010); therefore, our analysis, together with these findings, highlights the need for further research into the association of Ras and JNK status in cancer cell lines and the involvement of JNK signaling in Ras-dependent tumors.…”

Section: Discussionsupporting

confidence: 67%

Identification of Novel Ras-Cooperating Oncogenes in Drosophila melanogaster: A RhoGEF/Rho-Family/JNK Pathway Is a Central Driver of Tumorigenesis

et al. 2011

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We have shown previously that mutations in the apico-basal cell polarity regulators cooperate with oncogenic Ras (Ras ACT ) to promote tumorigenesis in Drosophila melanogaster and mammalian cells. To identify novel genes that cooperate with Ras ACT in tumorigenesis, we carried out a genome-wide screen for genes that when overexpressed throughout the developing Drosophila eye enhance Ras ACT -driven hyperplasia. Ras ACT -cooperating genes identified were Rac1 Rho1, RhoGEF2, pbl, rib, and east, which encode cell morphology regulators. In a clonal setting, which reveals genes conferring a competitive advantage over wildtype cells, only Rac1, an activated allele of Rho1 (Rho1 ACT ), RhoGEF2, and pbl cooperated with Ras ACT , resulting in reduced differentiation and large invasive tumors. Expression of RhoGEF2 or Rac1 with Ras ACT upregulated Jun kinase ( JNK) activity, and JNK upregulation was essential for cooperation. However, in the whole-tissue system, upregulation of JNK alone was not sufficient for cooperation with Ras ACT , while in the clonal setting, JNK upregulation was sufficient for Ras ACT -mediated tumorigenesis. JNK upregulation was also sufficient to confer invasive growth of Ras V12 -expressing mammalian MCF10A breast epithelial cells. Consistent with this, HER2 1 human breast cancers (where human epidermal growth factor 2 is overexpressed and Ras signaling upregulated) show a significant correlation with a signature representing JNK pathway activation. Moreover, our genetic analysis in Drosophila revealed that Rho1 and Rac are important for the cooperation of RhoGEF2 or Pbl overexpression and of mutants in polarity regulators, Dlg and aPKC, with Ras ACT in the whole-tissue context. Collectively our analysis reveals the importance of the RhoGEF/ Rho-family/JNK pathway in cooperative tumorigenesis with Ras ACT .

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Section: Discussionsupporting

confidence: 67%

Identification of Novel Ras-Cooperating Oncogenes in Drosophila melanogaster: A RhoGEF/Rho-Family/JNK Pathway Is a Central Driver of Tumorigenesis

et al. 2011

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“…The MKK4 gene has been identified previously as a putative human metastasis suppressor in prostate cancer (21,(39)(40)(41) and other forms of cancer (42)(43)(44). Moreover, mutations in JNK pathway genes (MKK4, MKK7, JNK1, and JNK2) have also been identified in human prostate cancer (45)(46)(47).…”

Section: Jnk Regulates the Tumorigenic Potential Of δPten Prostate Tumormentioning

confidence: 97%

JNK and PTEN cooperatively control the development of invasive adenocarcinoma of the prostate

Hübner

Mulholland

Standen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The c-Jun NH 2 -terminal kinase (JNK) signal transduction pathway is implicated in cancer, but the role of JNK in tumorigenesis is poorly understood. Here, we demonstrate that the JNK signaling pathway reduces the development of invasive adenocarcinoma in the phosphatase and tensin homolog (Pten) conditional deletion model of prostate cancer. Mice with JNK deficiency in the prostate epithelium (ΔJnk ΔPten mice) develop androgen-independent metastatic prostate cancer more rapidly than control (ΔPten) mice. Similarly, prevention of JNK activation in the prostate epithelium (ΔMkk4 ΔMkk7 ΔPten mice) causes rapid development of invasive adenocarcinoma. We found that JNK signaling defects cause an androgen-independent expansion of the immature progenitor cell population in the primary tumor. The JNK-deficient progenitor cells display increased proliferation and tumorigenic potential compared with progenitor cells from control prostate tumors. These data demonstrate that the JNK and PTEN signaling pathways can cooperate to regulate the progression of prostate neoplasia to invasive adenocarcinoma.T he c-Jun NH 2 -terminal kinase (JNK) signaling pathway can target members of the activating protein 1 (AP1) group of transcription factors, including ATF2, c-Jun, JunB, and JunD (1). These transcription factors represent an important component of the immediate-early gene response to mitogens and inflammatory stimuli (2). AP1 transcription factors are also implicated in dysregulated growth and tumor development (2). Significantly, JNK deficiency suppresses AP1-dependent gene expression and causes defects in cell proliferation, senescence, and apoptosis (3-5). JNK may, therefore, play a role in carcinogenesis.Studies using mouse models of cancer have confirmed that JNK can play a key role in cancer. Thus, JNK deficiency reduces the development of Bcr/Abl-induced lymphoma (6) and KRas-induced lung tumors (7). Moreover, carcinogen-induced hepatocellular carcinoma (8-10) and skin cancer (11) can be reduced by JNK deficiency. These observations demonstrate that JNK can promote cancer. However, loss of JNK signaling can also promote development of other tumors (2, 9, 12-15). These opposing roles of JNK in tumor development (promotion or repression) may represent differences in JNK function between tumor types (1). Alternatively, these differences may reflect separate functions of JNK in tumor cells and the tumor microenvironment (9).Mutational inactivation of the tumor suppressor phosphatase and tensin homolog (PTEN) frequently occurs in human prostate cancer (16)(17)(18). Mouse models of Pten deficiency in the prostate epithelium demonstrate that loss of PTEN expression is sufficient to cause activation of the AKT signaling pathway, prostatic intraepithelial neoplasia (PIN) lesions, and subsequent development of castration-resistant prostate cancer (19). Loss of PTEN function is, therefore, established to be a key step in the development of prostate cancer. Importantly, PTEN inactivation is associated with increased activity of the...

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“…MKK4 mRNA is expressed in most adult tissues with high expression in central nervous system and liver during embryonic development [9]. MAP2K4 mutations have been reported in some tumor cells, including pancreas, ovary, prostate and breast cancers, and its role in suppression of metastasis has been proposed in prostate and ovarian npg cancers [7]. However, there also exists evidence for oncogenic function of MKK4.…”

mentioning

confidence: 99%

“…Through an RNAi screen, the authors further found that the MAPKK, MKK4, provides key signaling for Vacquinol-1-induced macropinocytosis. MKK4 belongs to the Ser/Thr protein kinase family and is activated by environmental stress and inflammatory signals [7]. Upon activation, MKK4 phosphorylates downstream MAP kinases, such as JNK1/2 and p38, but not Erk1/2 [8].…”

mentioning

confidence: 99%