Hepatocyte growth factor/scatter factor activates proliferation in melanoma cells through p38 MAPK, ATF-2 and cyclin D1

Recio, Juan A.; Merlino, Glenn

doi:10.1038/sj.onc.1205150

Cited by 179 publications

(163 citation statements)

References 68 publications

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“…However, blocking a single network node is sufficient to perturb cellular responses, indicating that the targeted inhibition of a specific signalling pathway cannot be compensated for by other, still active, regulatory tiers. This is in line with the well-established observation that obstruction of individual MET-dependent pathways adversely affects tumour growth, survival and migration in various cancer cell types and under different experimental settings 37,48,50,56,57,58,70,71,72,76,139 . For example, the integrity of JNK-and p38-dependent signals is required for MET-stimulated proliferation and anchorage-independent growth in MET-transformed fibroblasts and melanoma cells 70,71,72 , and STAT3 signalling and NF-κB activity are necessary for MET-induced onset of leiomyosarcomas and for the survival of prostate cancer cells, respectively 48,76 .…”

Section: Met Signalling In Development and Diseasesupporting

confidence: 87%

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MET signalling: principles and functions in development, organ regeneration and cancer

Trusolino

Bertotti

Comoglio

2010

Nat Rev Mol Cell Biol

1,058

1,076

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The MET tyrosine kinase receptor (also known as the HGF receptor) promotes tissue remodelling, which underlies developmental morphogenesis, wound repair, organ homeostasis and cancer metastasis, by integrating growth, survival and migration cues in response to environmental stimuli or cell-autonomous perturbations. The versatility of MET-mediated biological responses is sustained by qualitative and quantitative signal modulation. Qualitative mechanisms include the engagement of dedicated signal transducers and the subcellular compartmentalization of MET signalling pathways, whereas quantitative regulation involves MET partnering with adaptor amplifiers or being degraded through the shedding of its extracellular domain or through intracellular ubiquitylation. Controlled activation of MET signalling can be exploited in regenerative medicine, whereas MET inhibition might slow down tumour progression.Throughout embryogenesis, cells bud off from developing tissues and move outwards to shape and pattern the complex architecture of prospective organs 1 . A similar process occurs in adult life during wound healing and tissue repair, when lingering cells migrate into injury sites to recreate the pre-existing structures 2 . The acquisition of cell motility is necessary, but not sufficient, for this event. Cells that detach from their neighbours must elude anoikis, a form of apoptotic cell death that occurs when cells lose adhesion with the extracellular matrix 3 . Moreover, migratory cells undergo extensive mitotic divisions to produce 'founder populations', which settle in newly forming organs during development or colonize worn tissues during repair 4,5 . The normal phases of embryogenesis and organ regeneration strongly resemble the pathological process of tumour invasiveness: similarly to cells at the wound edge, cells at the tumour's leading front disrupt intercellular contacts and infiltrate the adjacent surroundings, where they resist anoikis and grow before lodging in the blood vessels for systemic dissemination 6 . This resemblance is not simply a biological correlate, it has a common mechanistic basis: cancer cells resurrect the latent schemes of cellular reorganization, which are usually confined to embryonic development and damaged adult organs, and leverage them to become competent for metastasization 7 . The activities -motility, survival and proliferation -that occur in developing, injured and neoplastic tissues embody a biological programme that is defined as 'invasive growth' 8 . This is triggered by extracellular stimuli that regulate the activity of several transcription factors that, in turn, modulate the expression of a number of proteins, ranging from cytoskeletal and cell-cell junctional components to cell cycle regulators and anti-apoptotic effectors 9, 10 . One major environmental inducer of invasive growth is hepatocyte growth factor (HGF, also known as scatter factor), the ligand for the MET tyrosine kinase receptor (also known as the HGF receptor) 11,12,13,14,15,16,17,18,19,20 (Box 1). ...

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Section: Met Signalling In Development and Diseasesupporting

confidence: 87%

“…2a). Following MET-dependent stimulation, the JNKs and p38s control a range of cellular processes as diverse as cell proliferation, differentiation, transformation and apoptosis 70,71,72,73,74 .…”

mentioning

confidence: 99%

MET signalling: principles and functions in development, organ regeneration and cancer

Trusolino

Bertotti

Comoglio

2010

Nat Rev Mol Cell Biol

1,058

1,076

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“…The stress kinases p38 and c-Jun N-terminal kinase (JNK), which are occasionally activated by growth factors (33), can also activate the transcription factor ELK1 in some cell lines. Therefore, we performed a LUC-based GAL-ATF2 reporter assay that only differs from the one described above in that the second plasmid codes for GAL4 binding domain fused to the activation domain of ATF2 transcription factor.…”

Section: Edi Exon Inclusion Inmentioning

confidence: 99%

Mammary Epithelial-Mesenchymal Interaction Regulates Fibronectin Alternative Splicing via Phosphatidylinositol 3-Kinase

Blaustein

Pelisch

Coso

et al. 2004

Journal of Biological Chemistry

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The way alternative splicing is regulated within tissues is not understood. A relevant model of this process is provided by fibronectin, an important extracellular matrix protein that plays a key role in cell adhesion and migration and contains three alternatively spliced regions known as EDI, EDII, and IIICS. We used a cell culture system to simulate mammary epithelial-stromal communication, a process that is crucial for patterning and function of the mammary gland, and studied the effects of extracellular signals on the regulation of fibronectin pre-mRNA alternative splicing. We found that soluble factors from a mammary mesenchymal cell-conditioned medium, as well as the growth factors HGF/SF (hepatocyte growth factor/scatter factor), KGF (keratinocyte growth factor), and aFGF (acidic fibroblast growth factor), stimulate EDI and IIICS but not EDII inclusion into fibronectin mRNA in the mammary epithelial cell line SCp2, favoring fibronectin isoforms associated with proliferation, migration, and tissue remodeling. We explored the signaling pathways involved in this regulation and found that the mammary mesenchymal cell-conditioned medium and HGF/SF act through a phosphatidylinositol 3-kinase-dependent cascade to alter fibronectin alternative splicing. This splicing regulation is independent from promoter structure and de novo protein synthesis but does require two exonic elements within EDI. These results shed light on how extracellular stimuli are converted into changes in splicing patterns.Pre-mRNA alternative splicing is a widespread process that regulates gene expression and is the most important source of protein diversity in vertebrates (1). Fibronectin (FN), 1 the best characterized extracellular matrix (ECM) glycoprotein, plays a key role in cell adhesive and migratory behavior related to fundamental processes such as embryogenesis, wound healing, maintenance of tissue integrity, and malignancy. Different FN polypeptides arise through an intricate pattern of alternative splicing in three regions of the single primary transcript, (from 5Ј to 3Ј) extra domain II (EDII), extra domain I (EDI), and type III connecting segment (IIICS) (also called EDB or EIIIB, EDA or EIIIA, and V region, respectively), resulting in up to 12 variants in rodents. FN alternative splicing is modulated in a cell type-, development-, and age-specific manner and therefore constitutes a paradigm for studying the regulation of this complex process (2). EDI and EDII are cassette exons, either excluded from or included into the mature FN mRNA. The third site of alternative splicing, IIICS, is subject to total inclusion, partial inclusion, or total exclusion due to the presence of an internal 3Ј splice site within this exon.In vivo EDIϩ FN is poorly represented in the ECM of adult normal tissues. However, this variant is over-expressed in developing embryos, wound healing, liver fibrosis, ovary granulosa cell proliferation, and some tumors (2, 3). It has been proposed that EDI inclusion may mediate a conformational change in the whole m...

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“…For example, there is evidence for a role of p38 in the regulation of cyclin D1 protein ubiquitination and subsequent degradation through direct phosphorylation of a threonine residue (Casanovas et al, 2000). Furthermore, both positive (Crawley et al, 1997;Maher, 1999;Juretic et al, 2001;Recio and Merlino, 2002;Zhao et al, 2002) and negative (Diehl et al, 2000;Puri et al, 2000;Alderton et al, 2001;Smalley and Eisen, 2002) roles of p38 in cell proliferation have been described, suggesting that the mitogenic and antimitogenic functions of p38 are dependent on the cell type and possibly other factors.…”

mentioning

confidence: 99%

“…These effects are likely mediated, at least in part, by direct and/or indirect regulation of cell-cycle genes. For example, p38 was shown to promote melanoma and breast cancer cell proliferation through ATF-2-mediated upregulation of cyclin D1 (Recio and Merlino, 2002). However, p38 involvement in cell-cycle regulation is likely more complex and still not well explored.…”

mentioning

confidence: 99%

p38 MAP kinase signaling is necessary for rat chondrosarcoma cell proliferation

et al. 2004

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Chondrosarcomas represent the second most frequent class of primary skeletal malignancies. This tumor type is highly resistant to radiation therapy and currently available chemotherapies, thereby limiting treatment choice to surgical resection. Identifying the mechanisms responsible for chondrosarcoma cell proliferation is therefore crucial for the development of new treatment strategies. Here, we demonstrate a significant reduction in rat chondrosarcoma cell proliferation following treatment with pharmacological inhibitors (SB202190 and PD169316) of p38 mitogen-activated protein (MAP) kinases. In an attempt to dissect possible mechanisms, we investigated the effect of p38 inhibition on promoter activity of cell-cycle genes. Surprisingly, p38 inhibition resulted in upregulation of the activities of all three D-type cyclin promoters. In addition, p38 inhibitors induced increased transcription of the cell-cycle inhibitor p21 waf1/cip1 . As expected, promoter activity of the cyclin A gene, which lies downstream of D-type cyclins and p21 in cell-cycle progression, was strongly reduced by p38 inhibitors. These effects were independent of a cyclic AMP response element and conferred by the proximal 150 nucleotides of the cyclin A promoter. Decreased transcription was accompanied by greatly reduced cyclin A protein levels upon p38 inhibition. These observations indicate complex regulation of chondrosarcoma cell-cycle progression by p38 signaling, and suggest that components of p38 MAP kinase pathways may be effective targets in the treatment of these tumors.

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Hepatocyte growth factor/scatter factor activates proliferation in melanoma cells through p38 MAPK, ATF-2 and cyclin D1

Cited by 179 publications

References 68 publications

MET signalling: principles and functions in development, organ regeneration and cancer

MET signalling: principles and functions in development, organ regeneration and cancer

Mammary Epithelial-Mesenchymal Interaction Regulates Fibronectin Alternative Splicing via Phosphatidylinositol 3-Kinase

p38 MAP kinase signaling is necessary for rat chondrosarcoma cell proliferation

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