Gadd45a protects against UV irradiation-induced skin tumors, and promotes apoptosis and stress signaling via MAPK and p53.
Skin cancer is the most frequent form of malignancy in the world, and UV radiation is the primary environmental carcinogen responsible for its development. Herein we demonstrate that Gadd45a is a critical factor protecting the epidermis against UV radiation-induced tumorigenesis by promoting damaged keratinocytes to undergo apoptosis and/or cell cycle arrest, two crucial events that prevent the expansion of mutant or deregulated cells. Whereas Gadd45a has been implicated in cell cycle arrest, apoptosis, and DNA repair, to determine the physiological function of endogenous Gadd45a after genotoxic stress, the skin of Gadd45a-null mice was targeted with UV radiation. We report that Gadd45a induces apoptosis and cell cycle arrest by maintaining p38 and c-JNK MAPK activation in keratinocytes. The absence of Gadd45a results in loss of sustained p38/JNK MAPK activity beyond 15-30 min after UV radiation that leads to inadequate p53 activation and loss of normal activation of G(1) and G(2) checkpoints. Moreover, loss of Gadd45a dramatically reduces UV-induced apoptotic keratinocytes, "sunburn cells." Consequently, Gadd45a-null mice are more prone to tumors relative to wild-type mice. Therefore, we conclude that Gadd45a, like p53, is a key component protecting skin against UV-induced tumors.
Hildesheim
Jeffrey
J
Gene Response Section, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-4255, USA.
Bulavin
Dmitry V
DV
Anver
Miriam R
MR
Alvord
W Gregory
WG
Hollander
M Christine
MC
Vardanian
Lilit
L
Fornace
Albert J
AJ
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology* / Q000528:radiation effects; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology / Q000528:radiation effects; D018797:Cell Cycle Proteins; D004789:Enzyme Activation; D048031:JNK Mitogen-Activated Protein Kinases; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology / Q000528:radiation effects; D020935:MAP Kinase Signaling System / Q000502:physiology* / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D012867:Skin / Q000166:cytology / Q000528:radiation effects; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D015533:Transcriptional Activation / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014466:Ultraviolet Rays / Q000009:adverse effects*; D048051:p38 Mitogen-Activated Protein Kinases; D000097642:GADD45 Proteins
D018797:Cell Cycle Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D048051:p38 Mitogen-Activated Protein Kinases; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins