Journal
JOURNAL OF CELLULAR PHYSIOLOGY
Volume 212, Issue 1, Pages 76-88Publisher
WILEY
DOI: 10.1002/jcp.21004
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Protein tyrosine phosphatase IB (PTPIB) is a negative regulator of tyrosine kinase growth factor signaling. To assess the importance of PTPIB in the balance between death and survival in the liver, we have developed immortalized neonatal hepatocyte cell lines lacking (PTPIB-/-) or overexpressing (PTPIB+/+PTPIB) PTPIB. Early activation of caspase-3 occurred in PTPIB+/+PTPIB hepatocytes but was nearly abolished in PTPIB-/- cells. At the molecular level, PTPIB overexpression/deficiency altered the balance of pro-(Bim) and anti-(Bcl-x(L)) apoptotic members of the Bcl-2 family upon serum withdrawal. Likewise, cytosolic cytochrome C increased rapidly in PTPIB+/+PTPIB) hepatocytes whereas it was retained in the mitochondria of PTPIB-/- cells. DNA fragmentation and the increase of apoptotic cells induced by serum withdrawal in wild-type (PTPIB+/+) hepatocytes were absent in PTPIB-/- cells. Conversely, overexpression of PTPIB accelerated DNA laddering and increased the number of apoptotic cells. In serum-deprived PTPIB+/+PTPIB hepatocytes, a rapid entry of Foxo I into the nucleus and an earlier activation of caspase-8 was observed. However, both events were suppressed in PTPIB-/- hepatocytes. Moreover, PTPIB deficiency conferred resistance to apoptosis induced by activation of Fas and constitutively active Foxo 1. Rescue of PTPIB in deficient hepatocytes recovered the phenotype of wild-type cells whereas reduction of PTPIB by siRNA suppressed apoptosis. Our results reveal a unique role for PTPIB as a mediator of the apoptotic pathways triggered by trophic factors withdrawal in hepatocytes. This novel mechanism may represent an important target in the design of therapeutic strategies for human liver regeneration after pathological damage as well as for treatment of hepatocarcinomas.
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