CDIP, a novel pro-apoptotic gene, regulates TNFalpha-mediated apoptosis in a p53-dependent manner.
We have identified a novel pro-apoptotic p53 target gene named CDIP (Cell Death Involved p53-target). Inhibition of CDIP abrogates p53-mediated apoptotic responses, demonstrating that CDIP is an important p53 apoptotic effector. CDIP itself potently induces apoptosis that is associated with caspase-8 cleavage, implicating the extrinsic cell death pathway in apoptosis mediated by CDIP. siRNA-directed knockdown of caspase-8 results in a severe impairment of CDIP-dependent cell death. In investigating the potential involvement of extrinsic cell death pathway in CDIP-mediated apoptosis, we found that TNF-alpha expression tightly correlates with CDIP expression, and that inhibition of TNF-alpha signaling attenuates CDIP-dependent apoptosis. We also demonstrate that TNF-alpha is upregulated in response to p53 and p53 inducing genotoxic stress, in a CDIP-dependent manner. Consistently, knockdown of TNF-alpha impairs p53-mediated stress-induced apoptosis. Together, these findings support a novel p53 --> CDIP --> TNF-alpha apoptotic pathway that directs apoptosis after exposure of cells to genotoxic stress. Thus, CDIP provides a new link between p53-mediated intrinsic and death receptor-mediated extrinsic apoptotic signaling, providing a novel target for cancer therapeutics aimed at maximizing the p53 apoptotic response of cancer cells to drug therapy.
Brown
Lauren
L
Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
Ongusaha
Pat P
PP
Kim
Hyung-Gu
HG
Nuti
Shanthy
S
Mandinova
Anna
A
Lee
Ji Won
JW
Khosravi-Far
Roya
R
Aaronson
Stuart A
SA
Lee
Sam W
SW
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D001483:Base Sequence; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage; D004789:Enzyme Activation; D006801:Humans; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D053218:Receptors, Death Domain / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
D051017:Apoptosis Regulatory Proteins; C522864:CDIP1 protein, human; D053218:Receptors, Death Domain; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D053181:Caspase 8