TAILIEUCHUNG - Báo cáo khoa học: Proteolysis of the tumour suppressor hDlg in response to osmotic stress is mediated by caspases and independent of phosphorylation

Human disc-large (hDlg) is a scaffold protein critical for the maintenance of cell polarity and adhesion. hDlg is a component of the p38c MAP kinase pathway, which is important for the adaptation of mammalian cells to changes in environmental osmolarity. | Proteolysis of the tumour suppressor hDlg in response to osmotic stress is mediated by caspases and independent of phosphorylation Francisco A. Inesta-Vaquera1 Francisco Centeno2 Paloma del Reino1 Guadalupe Sabio3 Mark Peggie3 and Ana Cuenda1 3 1 Departamento de Inmunologia y Oncologia Centro Nacionalde Biotecnologia-CSIC Madrid Spain 2 Departamento Bioquimica y Biologia Molecular Universidad de Extremadura Caceres Spain 3 MRC Protein Phosphorylation Unit University of Dundee UK Keywords apoptosis caspase human disc-large osmotic shock p38-mitogen activated protein kinase Correspondence A. Cuenda Departamento de Inmunologia y Oncologia Centro Nacionalde Biotecnologia-CSIC Campus de Cantoblanco-UAM 28049-Madrid Spain Fax 34 91 372 0493 Tel 34 91 585 5451 E-mail acuenda@ Received 6 August 2008 revised 29 October 2008 accepted 7 November 2008 doi Human disc-large hDlg is a scaffold protein critical for the maintenance of cell polarity and adhesion. hDlg is a component of the p38y MAP kinase pathway which is important for the adaptation of mammalian cells to changes in environmental osmolarity. Here we report a strong decrease in the levels of hDlg protein in the human epithelial cell line HeLa when exposed to osmotic shock. This is independent of the phosphorylation state of hDlg is prevented by preincubating the cell with the caspase inhibitor z-VAD and is part of the apoptotic process triggered by cellular stress. Although both caspase 3 and caspase 6 are strongly activated by osmotic shock the time course of caspase 6 activation parallels hDlg degradation suggesting that this caspase may be responsible for the proteolysis. Mutating hDlg Asp747 to Ala abolishes caspase-induced cleavage but does not affect the early stage of apoptosis or cell attachment. Our findings show that osmotic stress triggers hDlg degradation through a mechanism different from the one mediated by proteasomes and we identify hDlg as a caspase .

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