p38 MAP kinase modulates Smad-dependent changes in human prostate cell adhesion

Hayes, Steven; Huang, Xiaoke; Kambhampati, Suman; Platanias, Leonidas C.; Bergan, Raymond C.

doi:10.1038/sj.onc.1206730

Cited by 53 publications

(54 citation statements)

References 65 publications

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“…We did not observe an effect of MYOCD on the miR143/ 145 enhancer carrying a CArG box mutation, suggesting that, in this context, MYOCD does not transactivate the SBE (data not shown). Finally, p38MAPK regulates the SMAD pathway via controlling the stability of SMAD3 (59). In this context, we noted a mild inhibition of phosphorylated SMAD2 in TGF-␤1-stimulated SMC pretreated with the SB203580 compound (data not shown).…”

Section: Discussionmentioning

confidence: 68%

Transforming Growth Factor-β1 (TGF-β1) Utilizes Distinct Pathways for the Transcriptional Activation of MicroRNA 143/145 in Human Coronary Artery Smooth Muscle Cells

Long

Miano

2011

Journal of Biological Chemistry

126

129

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MicroRNA 143/145 (miR143/145) is restricted to adult smooth muscle cell (SMC) lineages and mediates, in part, the expression of several SMC contractile genes. Although the function of miR143/145 has begun to be elucidated, its transcriptional regulation in response to various signaling inputs is poorly understood. In an effort to define a miR signature for SMC differentiation, we screened human coronary artery SMCs for miRs modulated by TGF-␤1, a known stimulus for SMC differentiation. Array analysis revealed a number of TGF-␤1-induced miRs, including miR143/145. Validation studies showed that TGF-␤1 stimulated miR143/145 expression in a dose-and time-dependent manner. We utilized several chemical inhibitors and found that SB203580, a specific inhibitor of p38MAPK, significantly decreased TGF-␤1-induced miR143/145 expression. siRNA studies demonstrated that the effect of TGF-␤1 on miR143/145 was dependent upon the myocardin and serum response factor transcriptional switch as well as SMAD4. TGF-␤1 stimulated a 580-bp human miR143/145 enhancer, and mutagenesis studies revealed a critical role for both a known CArG box and an adjacent SMAD-binding element for full TGF-␤1-dependent activation of the enhancer. Chromatin immunoprecipitation assays documented TGF-␤1-mediated enrichment of SMAD3 and SMAD4 binding over the enhancer region containing the SMAD-binding element. Pre-miR145 strongly promoted SMC differentiation, whereas an antimiR145 partially blocked TGF-␤1-induced SMC differentiation. These results demonstrate a dual pathway for TGF-␤1-induced transcription of miR143/145, thus revealing a novel mechanism underlying TGF-␤1-induced human vascular SMC differentiation. SMCs3 display remarkable phenotypic adaptation in response to physical, chemical, and biological perturbations. Such altered SMC phenotypes play a major role in the pathogenesis of many human diseases, including asthma, atherosclerosis, restenosis, hypertension, transplant arteriopathy, and Alzheimer angiopathy (1-3). Accumulating evidence has shown SMC differentiation to be tightly regulated by an interacting network of environmental stimuli, signaling pathways, and various transcription factors, most notably SRF and MYOCD (2, 4 -8). TGF-␤1 is among the most potent soluble growth factors that activate SMC contractile gene expression in both specified SMC and non-SMC types (9 -15). Members of the TGF-␤1 superfamily transmit signals through both SMADdependent and SMAD-independent pathways (16). The classic pathway is through transmembrane serine-threonine kinase receptors, which mediate the phosphorylation of receptor-specific SMAD2 and SMAD3. The phosphorylated SMAD2-SMAD3 complex then interacts with the common SMAD4 to form a heteromeric complex, which translocates to the nucleus and binds to Smad-binding elements (SBE) located in the regulatory region of a number of target genes (16). SMAD-independent pathways, such as MAPK and PI3K, can also be triggered by TGF-␤ to initiate signal transduction and gene regulation (17,18). Both SMAD-dependent ...

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Section: Discussionmentioning

confidence: 68%

Transforming Growth Factor-β1 (TGF-β1) Utilizes Distinct Pathways for the Transcriptional Activation of MicroRNA 143/145 in Human Coronary Artery Smooth Muscle Cells

Long

Miano

2011

Journal of Biological Chemistry

126

129

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“…Luciferase and b-gal activity were measured as described (Hayes et al, 2003), using luciferase and bgalactosidase Assay Systems (Promega, San Luis Obispo, CA, USA) as per the manufacturer's instructions.…”

Section: Smad Promoter Luciferase Reporter Assaysmentioning

confidence: 99%

Endoglin inhibits prostate cancer motility via activation of the ALK2-Smad1 pathway

et al. 2007

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Endoglin is a transforming growth factor b (TGFb) superfamily auxiliary receptor. We had previously shown that it suppressed prostate cancer (PCa) cell motility, and that its expression was lost during PCa progression. The mechanism by which endoglin inhibits PCa cell motility is unknown. Here we demonstrate that endoglin abrogates TGFb-mediated cell motility, but does not alter cell surface binding of TGFb. By measuring Smad-specific phosphorylation and Smad-responsive promoter activity, endoglin was shown to constitutively activate Smad1, with little-to-no effect upon Smad3. Knockdown of Smad1 increased motility and abrogated endoglin's effects. As type I activin receptor-like kinases (ALKs) are necessary for Smad activation, we went on to show that knockdown of ALK2, but not TGFbRI (ALK5), abrogated endoglinmediated decreases in cell motility and constitutively active ALK2 was sufficient to restore a low-motility phenotype in endoglin deficient cells. These findings provide the first evidence that endoglin decreases PCa cell motility through activation of the ALK2-Smad1 pathway.

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“…More specifically, Smad-7 acts as a scaffolding protein and facilitates the activation of the p38 MAPK pathway mediated by TGF-β-activated kinase 1 and MAPK-3 (Edlund et al, 2003). Then, p38 modulates the increased adhesion of metastatic PCa cells through phosphorylation and activation of Smad-3 (Hayes et al, 2003). It was also shown that Smad-7 interacts with growth arrest and DNA damage protein (GADD34), a regulatory/ targeting subunit of phospho-protein phosphatase 1 (PPP1).…”

Section: Tgf-βmentioning

confidence: 99%

Prostate cancer: the need for biomarkers and new therapeutic targets

Felgueiras

Silva

Fardilha

2014

J. Zhejiang Univ. Sci. B

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Prostate cancer (PCa) incidence and mortality have decreased in recent years. Nonetheless, it remains one of the most prevalent cancers in men, being a disquieting cause of men's death worldwide. Changes in many cell signaling pathways have a predominant role in the onset, development, and progression of the disease. These include prominent pathways involved in the growth, apoptosis, and angiogenesis of the normal prostate gland, such as androgen and estrogen signaling, and other growth factor signaling pathways. Understanding the foundations of PCa is leading to the discovery of key molecules that could be used to improve patient management. The ideal scenario would be to have a panel of molecules, preferably detectable in body fluids, that are specific and sensitive biomarkers for PCa. In the early stages, androgen deprivation is the gold standard therapy. However, as the cancer progresses, it eventually becomes independent of androgens, and hormonal therapy fails. For this reason, androgen-independent PCa is still a major therapeutic challenge. By disrupting specific protein interactions or manipulating the expression of some key molecules, it might be possible to regulate tumor growth and metastasis formation, avoiding the systemic side effects of current therapies. Clinical trials are already underway to assess the efficacy of molecules specially designed to target key proteins or protein interactions. In this review, we address that recent progress made towards understanding PCa development and the molecular pathways underlying this pathology. We also discuss relevant molecular markers for the management of PCa and new therapeutic challenges.

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p38 MAP kinase modulates Smad-dependent changes in human prostate cell adhesion

Cited by 53 publications

References 65 publications

Transforming Growth Factor-β1 (TGF-β1) Utilizes Distinct Pathways for the Transcriptional Activation of MicroRNA 143/145 in Human Coronary Artery Smooth Muscle Cells

Transforming Growth Factor-β1 (TGF-β1) Utilizes Distinct Pathways for the Transcriptional Activation of MicroRNA 143/145 in Human Coronary Artery Smooth Muscle Cells

Endoglin inhibits prostate cancer motility via activation of the ALK2-Smad1 pathway

Prostate cancer: the need for biomarkers and new therapeutic targets

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