NF-κB-mediated repression of growth arrest- and DNA-damage-inducible proteins 45α and γ is essential for cancer cell survival
- 7 September 2004
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 101 (37), 13618-13623
- https://doi.org/10.1073/pnas.0402069101
Abstract
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.This publication has 30 references indexed in Scilit:
- Bacterial photosynthesis genes in a virusNature, 2003
- Increased nuclear factor-κB activation is related to the tumor development of renal cell carcinomaCarcinogenesis: Integrative Cancer Research, 2003
- GADD45-induced cell cycle G2-M arrest associates with altered subcellular distribution of cyclin B1 and is independent of p38 kinase activityOncogene, 2002
- NF-κB regulation in the immune systemNature Reviews Immunology, 2002
- Inhibition of orthotopic growth and metastasis of androgen‐sensitive human prostate tumors in mice by bioactive soybean componentsThe Prostate, 2002
- Regulation of MTK1/MEKK4 Kinase Activity by Its N-Terminal Autoinhibitory Domain and GADD45 BindingMolecular and Cellular Biology, 2002
- NF-κB in cancer: from innocent bystander to major culpritNature Reviews Cancer, 2002
- Control of oncogenesis and cancer therapy resistance by the transcription factor NF-κBJCI Insight, 2001
- In Vivo Gene Delivery and Stable Transduction of Nondividing Cells by a Lentiviral VectorScience, 1996
- Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosisNature, 1996