Bcl-xL Blocks Transforming Growth Factor-β1-induced Apoptosis by Inhibiting Cytochrome c Release and not by Directly Antagonizing Apaf-1-dependent Caspase Activation in Prostate Epithelial Cells

Jerry E. Chipuk, Manjunatha Bhat, Andrew Y. Hsing, Jianjie Ma, David Danielpour

Research output: Contribution to journalArticlepeer-review

89 Scopus citations

Abstract

The mechanism by which transforming growth factor-β1 (TGF-β1) induces apoptosis of prostate epithelial cells was studied in the NRP-154 rat prostate epithelial cell line. TGF-β1 down-regulates expression of Bcl-xL and poly(ADP-ribosyl)polymerase (PARP), promotes cytochrome c release, up-regulates expression of latent caspase-3, and activates caspases 3 and 9. We tested the role of Bcl-xL in this cascade by stably overexpressing Bcl-xL to prevent loss by TGF-β1. Clones overexpressing Bcl-xL are resistant to TGF-β1 with respect to induction of apoptosis, cytochrome c release, activation of caspases 9 and 3, and cleavage of PARP; yet they remain sensitive to TGF-β1 by cell cycle arrest, induction of both fibronectin and latent caspase-3 expression, and loss of PARP expression. We show that Bcl-xL associates with Apaf-1 in NRP-154 cells; but this association does not inhibit the activation of caspases 9 and 3 by cytochrome c. Together, our data suggest that TGF-β1 induces apoptosis through loss of Bcl-xL, leading to cytochrome c release and the subsequent activation of caspases 9 and 3. Moreover, our data demonstrate that the antiapoptotic effect of Bcl-xL occurs by inhibition of mitochondrial cytochrome c release and not through antagonizing Apaf-1-dependent processing of caspases 9 and 3.

Original languageEnglish
Pages (from-to)26614-26621
Number of pages8
JournalJournal of Biological Chemistry
Volume276
Issue number28
DOIs
StatePublished - 13 Jul 2001
Externally publishedYes

Fingerprint

Dive into the research topics of 'Bcl-xL Blocks Transforming Growth Factor-β1-induced Apoptosis by Inhibiting Cytochrome c Release and not by Directly Antagonizing Apaf-1-dependent Caspase Activation in Prostate Epithelial Cells'. Together they form a unique fingerprint.

Cite this