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      PPARβ activation inhibits melanoma cell proliferation involving repression of the Wilms’ tumour suppressor WT1

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          Abstract

          Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that strongly influence molecular signalling in normal and cancer cells. Although increasing evidence suggests a role of PPARs in skin carcinogenesis, only expression of PPARγ has been investigated in human melanoma tissues. Activation of PPARα has been shown to inhibit the metastatic potential, whereas stimulation of PPARγ decreased melanoma cell proliferation. We show here that the third member of the PPAR family, PPARβ/δ is expressed in human melanoma samples. Specific pharmacological activation of PPARβ using GW0742 or GW501516 in low concentrations inhibits proliferation of human and murine melanoma cells. Inhibition of proliferation is accompanied by decreased expression of the Wilms’ tumour suppressor 1 (WT1), which is implicated in melanoma proliferation. We demonstrate that PPARβ directly represses WT1 as (1) PPARβ activation represses WT1 promoter activity; (2) in chromatin immunoprecipitation and electrophoretic mobility shift assays, we identified a binding element for PPARβ in the WT1 promoter; (3) deletion of this binding element abolishes repression by PPARβ and (4) the WT1 downstream molecules nestin and zyxin are down-regulated upon PPARβ activation. Our findings elucidate a novel mechanism of signalling by ligands of PPARβ, which leads to suppression of melanoma cell growth through direct repression of WT1.

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          AMPK and PPARdelta agonists are exercise mimetics.

          The benefits of endurance exercise on general health make it desirable to identify orally active agents that would mimic or potentiate the effects of exercise to treat metabolic diseases. Although certain natural compounds, such as reseveratrol, have endurance-enhancing activities, their exact metabolic targets remain elusive. We therefore tested the effect of pathway-specific drugs on endurance capacities of mice in a treadmill running test. We found that PPARbeta/delta agonist and exercise training synergistically increase oxidative myofibers and running endurance in adult mice. Because training activates AMPK and PGC1alpha, we then tested whether the orally active AMPK agonist AICAR might be sufficient to overcome the exercise requirement. Unexpectedly, even in sedentary mice, 4 weeks of AICAR treatment alone induced metabolic genes and enhanced running endurance by 44%. These results demonstrate that AMPK-PPARdelta pathway can be targeted by orally active drugs to enhance training adaptation or even to increase endurance without exercise.
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            Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma.

            To revise the staging system for cutaneous melanoma under the auspices of the American Joint Committee on Cancer (AJCC). The prognostic factors analysis described in the companion publication (this issue), as well as evidence from the published literature, was used to assemble the tumor-node-metastasis criteria and stage grouping for the melanoma staging system. Major changes include (1) melanoma thickness and ulceration but not level of invasion to be used in the T category (except for T1 melanomas); (2) the number of metastatic lymph nodes rather than their gross dimensions and the delineation of clinically occult (ie, microscopic) versus clinically apparent (ie, macroscopic) nodal metastases to be used in the N category; (3) the site of distant metastases and the presence of elevated serum lactic dehydrogenase to be used in the M category; (4) an upstaging of all patients with stage I, II, and III disease when a primary melanoma is ulcerated; (5) a merging of satellite metastases around a primary melanoma and in-transit metastases into a single staging entity that is grouped into stage III disease; and (6) a new convention for defining clinical and pathologic staging so as to take into account the staging information gained from intraoperative lymphatic mapping and sentinel node biopsy. This revision will become official with publication of the sixth edition of the AJCC Cancer Staging Manual in the year 2002.
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              Peroxisome proliferator-activated receptor delta controls muscle development and oxidative capability.

              Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors exerting several functions in development and metabolism. The physiological functions of PPARdelta remain elusive. By using a CRE-Lox recombination approach, we generated an animal model for muscle-specific PPARdelta overexpression to investigate the role of PPARdelta in this tissue. Muscle-specific PPARdelta overexpression results in a profound change in fiber composition due to hyperplasia and/or shift to more oxidative fiber and, as a consequence, leads to the increase of both enzymatic activities and genes implicated in oxidative metabolism. These changes in muscle are accompanied by a reduction of body fat mass, mainly due to a large reduction of adipose cell size. Furthermore, we demonstrate that endurance exercise promotes an accumulation of PPARdelta protein in muscle of wild-type animals. Collectively, these results suggest that PPARdelta plays an important role in muscle development and adaptive response to environmental changes, such as training exercise. They strongly support the idea that activation of PPARdelta could be beneficial in prevention of metabolic disorders, such as obesity or type 2 diabetes.
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                Author and article information

                Contributors
                +33-493-818498 , +33-493-815432 , nwagner@unice.fr
                Journal
                Pflugers Arch
                Pflugers Archiv
                Springer-Verlag (Berlin/Heidelberg )
                0031-6768
                1432-2013
                12 January 2010
                12 January 2010
                April 2010
                : 459
                : 5
                : 689-703
                Affiliations
                [1 ]Université de Nice-Sophia Antipolis, 06108 Nice, France
                [2 ]Department of Pathology, CHU Nice, 06107 Nice, France
                [3 ]Department of Human Pathology and Oncology, University of Florence, 50134 Florence, Italy
                [4 ]INSERM U907, 06107 Nice, France
                [5 ]INSERM U907, Faculté de Médecine, Université de Nice-Sophia Antipolis, 28, Avenue Valombrose, 06107 Nice, France
                Article
                776
                10.1007/s00424-009-0776-6
                2842567
                20066433
                df3f0699-d8b5-417c-a456-e6d1cd20134d
                © The Author(s) 2010
                History
                : 19 August 2009
                : 30 November 2009
                : 15 December 2009
                Categories
                Molecular and Genomic Physiology
                Custom metadata
                © Springer-Verlag 2010

                Anatomy & Physiology
                wt1,cancer cells,transcriptional regulation,skin,tumour,immunohistochemistry,proliferation,cell line,melanoma,pparβ

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