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Papers In Press, published online ahead of print July 11, 2006
Institute of Laboratory Medicine and Pathobiochemistry, Charité - Campus Benjamin Franklin, Berlin, Berlin 12200
Corresponding Author: otmar.huber{at}charite.de
Hint1 is a member of the evolutionary conserved family of histidine triad proteins which acts as a haplo-insufficient tumor suppressor inducing spontaneous tumor formation in Hint +/- and Hint -/- mouse models. However, the molecular mechanisms for the tumor suppressing activity are poorly defined. In this respect we recently showed that Hint1 by interaction with pontin and Reptin inhibits TCF/ß-catenin-mediated transcription of Wnt target genes. In this study we find that after transient transfection with Hint1 SW480 and MCF-7 cells undergo apoptosis as analyzed by pro-caspase-3 and PARP cleavage, M30 CytoDeath staining, cytochrome c release and DNA-fragmentation ELISA. Hint1 is involved in regulation of apoptotic pathways by inducing an up-regulation of p53 expression coinciding with an up-regulation of the pro-apoptotic factor Bax and a concomitant down-regulation of the apoptosis inhibitor Bcl-2. Bad and Puma levels remained unchanged. Further analyses revealed that Hint1 is associated with the Bax promoter and is a component of the Tip60 histone acetyltransferase complex and in this context appears to be involved in the regulation of Bax expression. Knock-down of Hint1 by shRNA results in down-regulation of p53 and Bax but had no effect on Bcl-2 expression. A mutant Hint1 (H112N) protein defective in the enzymatic activity as an AMP-NH2 hydrolase was not impaired in induction of apoptosis suggesting that the Hint1 pro-apoptotic activity is independent of the Hint1 enzymatic activity.
J. Biol. Chem, 10.1074/jbc.M513452200
Submitted on December 19, 2005
Accepted on July 11, 2006
The histidine triad protein Hint1 triggers apoptosis independent of its enzymatic activity
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