NF-kappa B-mediated repression of growth arrest- and DNA-damage-inducible proteins 45alpha and gamma is essential for cancer cell survival.
The NF-kappaB/IkappaB signaling pathway is a critical regulator of cell survival in cancer. Here, we report that combined down-regulation of growth arrest- and DNA-damage-inducible proteins (GADD)45alpha and gamma expression by NF-kappaB is an essential step for various cancer types to escape programmed cell death. We demonstrate that inhibition of NF-kappaB in cancer cells results in GADD45alpha- and gamma-dependent induction of apoptosis and inhibition of tumor growth. Inhibition of GADD45alpha and gamma in cancer cells by small interfering RNA abrogates apoptosis induction by the inhibitor of NF-kappaB and blocks c-Jun N-terminal kinase activation, whereas overexpression of GADD45alpha and gamma activates c-Jun N-terminal kinase and induces apoptosis. These results establish an unambiguous role for the GADD45 family as an essential mediator of cell survival in cancer cells with implications for cancer chemotherapy and novel drug discovery.
Zerbini
Luiz F
LF
Beth Israel Deaconess Medical Center Genomics Center and New England Baptist Bone and Joint Institute, 4 Blackfan Circle, Boston, MA 02115, USA.
Wang
Yihong
Y
Czibere
Akos
A
Correa
Ricardo G
RG
Cho
Je-Yoel
JY
Ijiri
Kosei
K
Wei
Wanjang
W
Joseph
Marie
M
Gu
Xuesong
X
Grall
Franck
F
Goldring
Mary B
MB
Zhou
Jin-Rong
JR
Libermann
Towia A
TA
Zhou
Jin-Rhong
JR
D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D045744:Cell Line, Tumor; D002470:Cell Survival; D004249:DNA Damage; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D015398:Signal Transduction; D000097642:GADD45 Proteins
D020672:I-kappa B Proteins; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D000097642:GADD45 Proteins