1. ¹Department of Surgery, University of Texas Health Science Center, Houston, TX, USA
2. ²Mayo Clinic Comprehensive Cancer Center, Jacksonville, FL, USA
3. ³Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA

Correspondence: Dr TC Ko, Department of Surgery, The University of Texas Health Science Center at Houston, 5656 Kelly, 30S62008, Houston, TX 77026, USA. E-mail: Tien.C.Ko@uth.tmc.edu; Dr Y Cao, Department of Surgery, The University of Texas Health Science Center at Houston, MSB4.608, 6431 Fannin Street, Houston, TX 77030, USA. E-mail: Yanna.Cao@uth.tmc.edu

Received 24 March 2008; Revised 6 October 2008; Accepted 1 November 2008; Published online 12 January 2009.

Abstract

Transforming growth factor- (TGF-) regulates epithelial tissue homeostasis by activating processes that control cell cycle arrest, differentiation and apoptosis. Disruption of the TGF- signaling pathway often occurs in colorectal cancers. Earlier, we have shown that TGF- induces apoptosis through the transcription factor Smad3. Affymetrix oligonucleotide microarrays were used to identify TGF-/Smad3 target genes that regulate apoptosis in rat intestinal epithelial cells (RIE-1). We found that TGF- repressed the expression of the inhibitor of differentiation (Id) gene family. Knockdown of Id1 and Id2 gene expression induced apoptosis in RIE-1 cells, whereas overexpression of Id2 attenuated TGF--induced apoptosis. TranSignal Protein/DNA arrays were used to identify the hypoxia-inducing factor-1 (HIF-1) as a downstream target of TGF-. HIF-1 is a basic helix-loop-helix protein, and overexpression of Id2 blocked HIF-1 activation by TGF-. Furthermore, knockdown of HIF-1 blocked TGF--induced apoptosis. Thus, we have identified HIF-1 as a novel mediator downstream of Id2 in the pathway of TGF--induced apoptosis.