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This Article Full Text Full Text (PDF) All Versions of this Article: 292/1/G28    most recent 00437.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Cao, Y. Articles by Ko, T. C. Search for Related Content PubMed PubMed Citation Articles by Cao, Y. Articles by Ko, T. C.

HORMONES AND SIGNALING

Identification of apoptotic genes mediating TGF-/Smad3-induced cell death in intestinal epithelial cells using a genomic approach

Departments of ¹Surgery and ²Biochemistry and Molecular Biology, Sealy Center for Cancer Cell Biology, University of Texas Medical Branch, Galveston, Texas; ³Mayo Clinic, Jacksonville, Florida; and ⁴Department of Surgery, Texas A&M Health Science Center, Temple, Texas

Submitted 18 September 2005 ; accepted in final form 31 July 2006

Transforming growth factor (TGF)--dependent apoptosis is important in the elimination of damaged or abnormal cells from normal tissues in vivo. Previously, we have shown that TGF- inhibits the growth of rat intestinal epithelial (RIE)-1 cells. However, RIE-1 cells are relatively resistant to TGF--induced apoptosis due to a low endogenous Smad3-to-Akt ratio. Overexpression of Smad3 sensitizes RIE-1 cells (RIE-1/Smad3) to TGF--induced apoptosis by altering the Smad3-to-Akt ratio in favor of apoptosis. In this study, we utilized a genomic approach to identify potential downstream target genes that are regulated by TGF-/Smad3. Total RNA samples were analyzed using Affymetrix oligonucleotide microarrays. We found that TGF- regulated 518 probe sets corresponding to its target genes. Interestingly, among the known apoptotic genes included in the microarray analyses, only caspase-3 was induced, which was confirmed by real-time RT-PCR. Furthermore, TGF- activated caspase-3 through protein cleavage. Upstream of caspase-3, TGF- induced mitochondrial depolarization, cytochrome c release, and cleavage of caspase-9, which suggests that the intrinsic apoptotic pathway mediates TGF--induced apoptosis in RIE-1/Smad3 cells.

apoptosis; Affymetrix oligonucleotide microarrays; caspases; transforming growth factor-