AMP-activated protein kinase contributes to UV- and H2O2-induced apoptosis in human skin keratinocytes.
AMP-activated protein kinase or AMPK is an evolutionarily conserved sensor of cellular energy status, activated by a variety of cellular stresses that deplete ATP. However, the possible involvement of AMPK in UV- and H(2)O(2)-induced oxidative stresses that lead to skin aging or skin cancer has not been fully studied. We demonstrated for the first time that UV and H(2)O(2) induce AMPK activation (Thr(172) phosphorylation) in cultured human skin keratinocytes. UV and H(2)O(2) also phosphorylate LKB1, an upstream signal of AMPK, in an epidermal growth factor receptor-dependent manner. Using compound C, a specific inhibitor of AMPK and AMPK-specific small interfering RNA knockdown as well as AMPK activator, we found that AMPK serves as a positive regulator for p38 and p53 (Ser(15)) phosphorylation induced by UV radiation and H(2)O(2) treatment. We also observed that AMPK serves as a negative feedback signal against UV-induced mTOR (mammalian target of rapamycin) activation in a TSC2-dependent manner. Inhibiting mTOR and positively regulating p53 and p38 might contribute to the pro-apoptotic effect of AMPK on UV- or H(2)O(2)-treated cells. Furthermore, activation of AMPK also phosphorylates acetyl-CoA carboxylase or ACC, the pivotal enzyme of fatty acid synthesis, and PFK2, the key protein of glycolysis in UV-radiated cells. Collectively, we conclude that AMPK contributes to UV- and H(2)O(2)-induced apoptosis via multiple mechanisms in human skin keratinocytes and AMPK plays important roles in UV-induced signal transduction ultimately leading to skin photoaging and even skin cancer.
Cao
Cong
C
Department of Biology, Providence College, Providence, Rhode Island 02918-0001, USA.
Lu
Shan
S
Kivlin
Rebecca
R
Wallin
Brittany
B
Card
Elizabeth
E
Bagdasarian
Andrew
A
Tamakloe
Tyrone
T
Chu
Wen-ming
WM
Guan
Kun-liang
KL
Wan
Yinsheng
Y
D055372:AMP-Activated Protein Kinases / Q000737:chemistry*; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000263:Adenylate Kinase / Q000378:metabolism; D017209:Apoptosis; D002460:Cell Line; D004815:Epidermal Growth Factor / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry*; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism; D008954:Models, Biological; D012867:Skin / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016159:Tumor Suppressor Protein p53; D004815:Epidermal Growth Factor; D006861:Hydrogen Peroxide; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; D000263:Adenylate Kinase; D000103:Acetyl-CoA Carboxylase