title: CDIP, a novel pro-apoptotic gene, regulates TNFalpha-mediated apoptosis in a p53-dependent manner.
abstract: 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.
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Brown
authors.forename: Pat P
authors.initials: PP
authors.lastname: Ongusaha
authors.forename: Hyung-Gu
authors.initials: HG
authors.lastname: Kim
authors.forename: Shanthy
authors.initials: S
authors.lastname: Nuti
authors.forename: Anna
authors.initials: A
authors.lastname: Mandinova
authors.forename: Ji Won
authors.initials: JW
authors.lastname: Lee
authors.forename: Roya
authors.initials: R
authors.lastname: Khosravi-Far
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Aaronson
authors.forename: Sam W
authors.initials: SW
authors.lastname: Lee
mesh_terms: 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
chemical_list: 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