Singlet oxygen-induced attenuation of growth factor signaling: Possible role of ceramides

被引:40
作者
Schieke, SM
von Montfort, C
Buchczyk, DP
Timmer, A
Grether-Beck, S
Krutmann, J
Holbrook, NJ
Klotz, LO
机构
[1] Univ Dusseldorf, Inst Biochem & Mol Biol 1, D-40225 Dusseldorf, Germany
[2] Univ Dusseldorf gGmbH, IUF, D-40225 Dusseldorf, Germany
[3] Yale Univ, Sch Med, Dept Internal Med, Sect Geriatr, New Haven, CT 06520 USA
关键词
singlet oxygen; oxidative stress; ceramides; growth factors; MAPK; ERK;
D O I
10.1080/10715760410001712764
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Singlet oxygen, an electronically excited form of molecular oxygen, is a primary mediator of the activation of stress-activated protein kinases elicited by ultraviolet A (UVA; 320-400 nm). Here, the effects of singlet oxygen (O-1(2) ) on the extracellular signal-regulated kinase (ERK) 1/2 and Akt/protein kinase B pathways were analyzed in human dermal fibroblasts. While basal ERK 1/2 phosphorylation was lowered in cells exposed to either O-1(2) , UVA or photodynamic treatment, Akt was moderately activated by photochemically generated O-1(2) in a phosphoinositide 3-kinase (PI3K)-dependent fashion, resulting in the phosphorylation of glycogen synthase kinase-3 (GSK3). The activation of ERK 1/2 and Akt as induced by stimulation with epidermal growth factor (EGF) or platelet-derived growth factor (PDGF) was inhibited by O-1(2) generated intracellularly upon photoexcitation of rose Bengal (RB). Photodynamic therapy (PDT)-induced apoptosis is known to be associated with increased formation of ceramides. Likewise, both O-1(2) and UVA induced ceramide generation in human skin fibroblasts. The attenuation of EGF- and PDGF-induced activation of ERK 1/2 and Akt by O-1(2) was mimicked by stimulation of fibroblasts with the cell-permeable C-2 -ceramide. Interestingly, EGF-induced tyrosine phosphorylation of the EGF receptor was strongly attenuated by O-1(2) but unimpaired by C-2 -ceramide, implying that, although ceramide formation may mediate the above attenuation of ERK and Akt phosphorylation induced by O-1(2) , mechanisms beyond ceramide formation exist that mediate impairment of growth factor signaling by singlet oxygen. In summary, these data point to a novel mechanism of O-1(2) toxicity: the known O-1(2)-induced activation of proapoptotic kinases such as JNK and p38 is paralleled by the prevention of activation of growth factor receptor-dependent signaling and of anti-apoptotic kinases, thus shifting the balance towards apoptosis.
引用
收藏
页码:729 / 737
页数:9
相关论文
共 52 条
[1]   Ceramide directly activates protein kinase C ζ to regulate a stress-activated protein kinase signaling complex [J].
Bourbon, NA ;
Yun, J ;
Kester, M .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (45) :35617-35623
[2]   Ceramide-induced inhibition of Akt is mediated through protein kinase Cζ -: Implications for growth arrest [J].
Bourbon, NA ;
Sandirasegarane, L ;
Kester, M .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (05) :3286-3292
[3]   Inhibitory actions of ceramide upon PKC-ε/ERK interactions [J].
Bourbon, NA ;
Yun, J ;
Berkey, D ;
Wang, YZ ;
Kester, M .
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 2001, 280 (06) :C1403-C1411
[4]   High efficiency of 5-aminolevulinate-photodynamic treatment using UVA irradiation [J].
Buchczyk, DP ;
Klotz, LO ;
Lang, K ;
Fritsch, C ;
Sies, H .
CARCINOGENESIS, 2001, 22 (06) :879-883
[5]   Long chain ceramides activate protein phosphatase-1 and protein phosphatase-2A - Activation is stereospecific and regulated by phosphatidic acid [J].
Chalfant, CE ;
Kishikawa, K ;
Mumby, MC ;
Kamibayashi, C ;
Bielawska, A ;
Hannun, YA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (29) :20313-20317
[6]   Apoptotic signalling cascade in photosensitized human epidermal carcinoma A431 cells: involvement of singlet oxygen, c-Jun N-terminal kinase, caspase-3 and p21-activated kinase 2 [J].
Chan, WH ;
Yu, JS ;
Yang, SD .
BIOCHEMICAL JOURNAL, 2000, 351 :221-232
[7]   Sphingolipid metabolites differentially regulate extracellular signal-regulated kinase and stress-activated protein kinase cascades [J].
Coroneos, E ;
Wang, YZ ;
Panuska, JR ;
Templeton, DJ ;
Kester, M .
BIOCHEMICAL JOURNAL, 1996, 316 :13-17
[8]   Cellular survival: a play in three Akts [J].
Datta, SR ;
Brunet, A ;
Greenberg, ME .
GENES & DEVELOPMENT, 1999, 13 (22) :2905-2927
[9]   UV-A-induced AP-1 activation requires the Raf/ERK pathway in human NCTC 2544 keratinocytes [J].
Djavaheri-Mergny, M ;
Dubertret, L .
EXPERIMENTAL DERMATOLOGY, 2001, 10 (03) :204-210
[10]  
DOBROWSKY RT, 1993, J BIOL CHEM, V268, P15523