The Mitogen Activated Protein Kinase (MAPK) module operates downstream of Ras to convey cell surface signals to the nucleus via the nuclear translocation of p42/p44 MAPKs. We have previously established that MAPK activation is obligatory and must persist in the G1 phase to allow resting fibroblasts to exit from G0 (Pagès et al., Proc. Natl. Acad. Sci.1993, 90, 8319-8323). It remained to be established whether MAPK activation was sufficient to trigger cell proliferation. To this aim, we generated and expressed in Chinese hamster lung fibroblasts, constitutively active mutants of hamster MAP kinase kinase (MAPKK). Three mutants: S218D, S222D and S218D/S222D in which we substituted the Raf1/MAPKKK-dependent regulatory phosphorylation sites by aspartic acid residues, displayed increased basal activity when expressed in fibroblasts. Two of them, S218D and S218D/S222D which have a basal activity higher than serum-stimulated wild type-MAPKK (respectively 2- and 5-fold), induced activation of p42 MAPK in growth factor-deprived cells. Interestingly, only these two mutants led to a growth factor-independent state as judged by early gene transcription (activation of the fos promoter), increased sensitivity to growth factors for reinitiation of DNA synthesis, autonomous cell cycling and rapid tumor formation in nude mice. Therefore we conclude that the downstream elements of the growth factor signalling cascade, MAPKK-MAPK, are both necessary and sufficient to promote growth factor signals and autonomous cell cycling in fibroblasts.
"The specific role of p38α MAPK regulated inflammatory response in facilitating tumor growth is directly related to TNF-α through cellular proliferation, differentiation , development and regulation of cell cycle. In recent years, activation of these signaling cascades has been noted in colon, ovary        and lung cancers . Besides, the p38α and p38δ MAPK show a role in promoting the malignant phenotype of squamous cell carcinoma and inhibition of p38α resulted in marked cell death in tumor tissue, removed after surgery . "
[Show abstract][Hide abstract] ABSTRACT: Translation of early findings from basic research is aimed to benefit cancer therapeutics. We report the p38α level in serum of head and neck squamous cell carcinoma (HNSCC) patients indicating it as a prognostic marker and established its correlation with radiation therapy (RT).
The case-controlled study was performed on 120 HNSCC patients from whom 81 patients and 45 controls were statistically analyzed. The p38α estimation was done at pre-RT, during-RT and post-RT using a real time Surface Plasmon Resonance (SPR) technology, ELISA and western blot.
HNSCC patients showed threefold increase in p38α level when compared to control (p value<0.0001). The estimated concentration of p38α in a temporal manner, before-RT, during-RT and post-RT was 0.61 ng/μl (95%CI: 0.53-0.69), 0.35 ng/μl (95%CI: 0.31-0.38) and 0.30 ng/μl (95%CI: 0.26-0.33), respectively. Among the 81 cases, 70 patients (86.42%) showed a declined p38α in response to RT as evaluated by SPR and were responding clinically (clinical tumor regression).
This study showed elevated p38α level at cancer diagnosis and a statistically significant decline during-RT and post-RT periods. Hence, it can emerge as a prognostic marker supporting the candidature of p38α as a suitable serum marker in HNSCC.
Clinica chimica acta; international journal of clinical chemistry 01/2012; 413(1-2):219-25. DOI:10.1016/j.cca.2011.09.031 · 2.82 Impact Factor
"As none of the Ras isoforms transformed Jnk2À/À MEFs, we continued to use H-Ras as a representative of the Ras family, which will from now on be referred to as Ras. Importantly, a constitutively active form of the Ras downstream effector MEK1, that transforms NIH3T3 cells (Brunet et al., 1994), was found to transform immortalized wt and Jnk1À/À MEFs but was not capable of transforming corresponding ATF2 and c-Myc co-operation in Ras transformation DP Mathiasen et al Jnk2À/À MEFs (Supplementary Figure 1a), even though ERK was strongly activated by Ras in immortalized Jnk2À/À MEFs, which was detected as increased ERK phosphorylation (Figure 1c). Some ERK activation was also detected in Jnk2À/À MEFs expressing control vector (À), which was probably due to increased expression of endogenous N-and K-Ras (Figure 1b). "
[Show abstract][Hide abstract] 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.
"Studies in cultured cells have revealed that expression of activated alleles of MEK1 or MEK2 is sufficient to deregulate the proliferation and trigger transformation of immortalized fibroblast and epithelial cell lines [15,31,32,63,64]. Orthotopic transplantation of mammary or intestinal epithelial cells expressing activated MEK1/MEK2 into mice induces the formation of aggressive tumors that progress up to the metastatic stage [15,64]. "
[Show abstract][Hide abstract] ABSTRACT: The Ras-dependent Raf/MEK/ERK1/2 mitogen-activated protein (MAP) kinase signaling pathway is a major regulator of cell proliferation and survival. Not surprisingly, hyperactivation of this pathway is frequently observed in human malignancies as a result of aberrant activation of receptor tyrosine kinases or gain-of-function mutations in RAS or RAF genes. Components of the ERK1/2 pathway are therefore viewed as attractive candidates for the development of targeted therapies of cancer. In this article, we briefly review the basic research that has laid the groundwork for the clinical development of small molecules inhibitors of the ERK1/2 pathway. We then present the current state of clinical evaluation of MEK1/2 inhibitors in cancer and discuss challenges ahead.
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