The Raf/MEK/ERK pathway: new concepts of activation

Peyssonnaux, Carole; Eychène, Alain

doi:10.1016/s0248-4900(01)01125-x

Cited by 658 publications

(471 citation statements)

References 107 publications

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“…MEK1 and MEK2 are protein kinases that when activated (phosphorylated) are believed to dually phosphorylate only ERK1 and ERK2, thereby increasing the enzymatic activity of ERKs approximately 1000-fold over the activity found with the basal or monophosphorylated forms (Traverse et al, 1992;Lenormand et al, 1993, Robbins et al, 1993. The consequence is a phosphorylation of diverse protein kinases, transcription factors, and even cytoskeletal proteins leading to paradoxical cellular responses ranging from proliferation to apoptosis (Peyssonnaux and Eychene, 2001;Djeu et al, 2002;Lee and McCubrey, 2002). Interestingly, similar conflicting reports also exist on the role of the MEKs and ERKs in CDDP-induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…Originally the ERK module was thought to mediate cell proliferation and differentiation. Recent data, however, clearly show that the ERK activation culminates in phosphorylation of many proteins with substantial regulatory functions throughout the cell, coordinating and eliciting conflicting cellular responses ranging from proliferation and differentiation to apoptosis (Peyssonnaux and Eychene, 2001;Djeu et al, 2002;Lee and McCubrey, 2002). Here, we show that in NCCIT cells, CDDP activates the MEK -ERK signalling pathway, which is followed by a caspase 3-mediated apoptosis.…”

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confidence: 99%

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Cisplatin-induced apoptosis in human malignant testicular germ cell lines depends on MEK/ERK activation

et al. 2004

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Testicular germ cell tumours (TGCT) represent the most common malignancies in young males. Whereas in 1970s, the survival rate in patients with metastatic testicular tumours was only 5%, these days, 80% of the patients treated by modern chemotherapy will survive their disease. The drug that revolutionised the cure rate for patients with metastatic testicular tumours was cisdiamminedichloroplatinum (cisplatin, CDDP). In vitro experiments on neoplastic germ cell lines showed that their exquisite sensitivity to CDDP could be attributed to p53-dependent and -independent pathways. Applying cDNA macroarray, semiquantitative RT -PCR and Western blot analyses, blocking experiments, caspase activity assays, and morphological methods, we sought here to define the p53-independent pathway(s) involved in the CDDP-induced apoptosis. For this purpose, we used the human TGCT cell line NCCIT, the mutated p53 of which is known to remain inactive during the course of CDDP-induced apoptosis. Our experiments showed that within hours of CDDP application, two prototype members of the 'mitogen-activated protein kinase' (MAPK) family, designated 'MAPK ERK kinase' (MEK) and 'extracellular signal-regulated kinase' (ERK), were dually phosphorylated and caspase-3 became active. Functional assays using MEK inhibitors demonstrated that the phosphorylation of MEK and ERK was required for the activation of caspase-3 as the executing caspase. Interestingly, experiments with the human malignant germ cell line NTERA, which is known to possess wild-type p53, revealed the same results. Thus, our data suggest that CDDP mediates its p53-independent apoptosis-inducing effect on the malignant human testicular germ cells -at least partially -through activation of the MEK -ERK signalling pathway.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Cisplatin-induced apoptosis in human malignant testicular germ cell lines depends on MEK/ERK activation

et al. 2004

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“…[9][10][11][12] BRAF encodes a serine-threonine kinase that acts in the mitogen activated protein kinase (MAPK) pathway. 13 Activating BRAF mutations induce constitutive activation of the signal transduction pathway, providing a potent promitogenic force that drives malignant transformation. 14,15 Activating mutations of the BRAF oncogene is the most common genetic alteration in well-differentiated thyroid carcinoma, but this alteration is highly tumor-type specific.…”

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confidence: 99%

BRAF mutations in anaplastic thyroid carcinoma: implications for tumor origin, diagnosis and treatment

et al. 2004

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Anaplastic thyroid carcinoma is a highly aggressive neoplasm. Affected patients typically present with advanced disease where there is little hope for cure using conventional therapeutic modalities. Understanding the genetic alterations underlying the development of anaplastic thyroid carcinoma, such as mutational activation of BRAF, could help clarify its relationship with well-differentiated forms of thyroid carcinoma (ie follicular and papillary carcinoma) and could help select patients most likely to benefit from novel therapeutic strategies targeting BRAF. We tested 16 anaplastic thyroid carcinomas for the thymine (T)-adenine (A) missense mutation at nucleotide 1796 in the BRAF gene using a newly developed assay that employs a novel primer extension method (Mutector s assay). Seven of these anaplastic thyroid carcinomas arose in association with a well-differentiated thyroid carcinoma, and these were also evaluated. The 1796T-A mutation was detected in eight (50%) of the anaplastic thyroid carcinomas, in four of five (80%) associated papillary thyroid carcinomas, and in zero of two (0%) associated follicular carcinomas. In all seven cases where anaplastic thyroid carcinoma arose in association with a well-differentiated thyroid carcinoma, BRAF status in the two components was concordant. Like papillary thyroid carcinoma, a significant percentage of anaplastic thyroid carcinomas also harbor BRAF mutations. Indeed, when papillary thyroid carcinoma and anaplastic thyroid carcinoma occur together, they consistently share the same BRAF profile, supporting the notion that many anaplastic thyroid carcinomas actually represent progressive malignant degeneration of a pre-existing welldifferentiated thyroid carcinoma. The high frequency of BRAF mutations in a tumor that is generally regarded as uniformly fatal justifies evaluation of the potential benefits of anti-BRAF therapy for patients with anaplastic thyroid carcinoma.

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“…Both KRAS and BRAF are members of the RAS-dependent mitogen-activated protein kinase pathway, which mediates cellular responses to growth signals. 31 KRAS belongs to the RAS family that encode guanosine-5′-triphosphate-binding proteins as an effector of ligand-bound EGFR. BRAF encodes a serine-threonine protein kinase that is a downstream effector of activated KRAS.…”

Section: Discussionmentioning

confidence: 99%

Cholangiocarcinoma with intraductal tubular growth pattern versus intraductal papillary growth pattern

et al. 2016

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Intraductal neoplasms of the bile duct are macroscopically characterized by exophytic or polypoid growth patterns and have a favorable prognosis. Although some tumors with a predominantly tubular microscopic pattern have been reported, they have not been well characterized clinicopathologically. The purpose of the present study was to compare the newly recognized cholangiocarcinoma with an intraductal tubular growth pattern and cholangiocarcinoma with an intraductal papillary growth pattern and to investigate the pathological and prognostic significance of the former. This study analyzed 161 patients with tumors with exophytic or polypoid growth patterns from a large series of 733 cholangiocarcinoma cases surgically resected from January 1998 to May 2013. The study patients were divided into two groups: those whose tumors showed a predominantly tubular growth pattern (n = 52) and those whose tumors exhibited a predominantly papillary growth pattern (n = 109). Tubular growth pattern was associated with combined vascular resection and the absence of macroscopic mucin. Several histological indexes were significantly higher for the tubular growth pattern than the papillary one, including tubular adenocarcinoma, depth of invasion, microscopic lymphatic invasion, venous invasion, perineural invasion, and necrosis. Although the survival curves overlapped (P = 0.693), the rate of liver metastasis was significantly higher for the tubular growth pattern than for the papillary one (P = 0.012). Genomic DNA analysis focusing on somatic mutations in codons 12 and 13 of KRAS and codon 600 of BRAF revealed only one (4%) KRAS and no BRAF mutation among the 25 tubular cases examined. In conclusion, the tubular growth pattern exhibited differences in some histologic indexes, in addition to a higher hepatic metastasis rate and a lower KRAS mutation frequency, compared with the papillary growth pattern, but no difference in prognosis was observed. The distinctiveness of this tubular neoplasm should be further examined in the future.

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The Raf/MEK/ERK pathway: new concepts of activation

Cited by 658 publications

References 107 publications

Cisplatin-induced apoptosis in human malignant testicular germ cell lines depends on MEK/ERK activation

Cisplatin-induced apoptosis in human malignant testicular germ cell lines depends on MEK/ERK activation

BRAF mutations in anaplastic thyroid carcinoma: implications for tumor origin, diagnosis and treatment

Cholangiocarcinoma with intraductal tubular growth pattern versus intraductal papillary growth pattern

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