Protein kinase C-α overexpression stimulates Akt activity and suppresses apoptosis induced by interleukin 3 withdrawal

被引:94
作者
Li, WQ
Zhang, JC
Flechner, L
Hyun, T
Yam, A
Franke, TF
Pierce, JH
机构
[1] NCI, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA
[2] Columbia Univ, Dept Pharmacol, New York, NY 10032 USA
关键词
apoptosis; Akt/protein kinase B; protein; kinase C-alpha;
D O I
10.1038/sj.onc.1203065
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
To investigate the role of protein kinase C (PKC) in apoptotic signaling induced by cytokine withdrawal, we expressed PKC-alpha, -delta and -epsilon individually in the 32D myeloid progenitor cells. The parental and PKC-delta- and PKC-epsilon- transfected 32D cells underwent apoptosis within 24 h in the absence of interleukin 3. In contrast, expression of PKC-alpha inhibited the onset of apoptosis as determined by genomic DNA fragmentation and flow cytometric analysis. Correlating with the inhibition of apoptosis, PKC-alpha transfectants exhibited increased activity of the endogenous Akt serine/threonine kinase. Furthermore, PKC-alpha, but not PKC-delta or -epsilon, specifically activated overexpressed Akt. PKC-alpha-induced Akt activity was partially dependent on phosphoinositol 3' kinase (PI 3'K) since a PI 3'K inhibitor was able to suppress PKC-alpha-induced Akt activation. Both basal and interleukin 3-stimulated phosphorylation of Akt on serine 473 was enhanced in the PKC-alpha and Akt contransfectants. Coexpression of wild type Akt and PKC-alpha resulted in greater suppression of apoptosis than PKC-alpha expression alone. Together, our results demonstrate that suppression of apoptosis by PKC-alpha correlates with its ability of activating endogenous Akt. Furthermore, activation of overexpressed Akt by PKC-alpha is consistent with their synergistic effect on suppressing apoptosis, providing the strong evidence of cross talk between Akt and PKC-alpha.
引用
收藏
页码:6564 / 6572
页数:9
相关论文
共 45 条
[31]  
MISCHAK H, 1993, J BIOL CHEM, V268, P20110
[32]   Proteolytic cleavage of protein kinase C isotypes, which generates kinase and regulatory fragments, correlates with Fas-mediated and 12-O-tetradecanoyl-phorbol-13-acetate-induced apoptosis [J].
Mizuno, K ;
Noda, K ;
Araki, T ;
Imaoka, T ;
Kobayashi, Y ;
Akita, Y ;
Shimonaka, M ;
Kishi, S ;
Ohno, S .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1997, 250 (01) :7-18
[33]   INTRACELLULAR SIGNALING BY HYDROLYSIS OF PHOSPHOLIPIDS AND ACTIVATION OF PROTEIN-KINASE-C [J].
NISHIZUKA, Y .
SCIENCE, 1992, 258 (5082) :607-614
[34]  
O'Brian CA, 1998, ONCOL REP, V5, P305
[35]   STRUCTURAL AND FUNCTIONAL DIVERSITIES OF A FAMILY OF SIGNAL TRANSDUCING PROTEIN-KINASES, PROTEIN-KINASE-C FAMILY - 2 DISTINCT CLASSES OF PKC, CONVENTIONAL CPKC AND NOVEL NPKC [J].
OHNO, S ;
AKITA, Y ;
HATA, A ;
OSADA, SI ;
KUBO, K ;
KONNO, Y ;
AKIMOTO, K ;
MIZUNO, K ;
SAIDO, T ;
KUROKI, T ;
SUZUKI, K .
ADVANCES IN ENZYME REGULATION, 1991, 31 :287-+
[36]   Advances in apoptosis research [J].
Peter, ME ;
Heufelder, AE ;
Hengartner, MO .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (24) :12736-12737
[37]   Phosphorylation and activation of p70s6k by PDK1 [J].
Pullen, N ;
Dennis, PB ;
Andjelkovic, M ;
Dufner, A ;
Kozma, SC ;
Hemmings, BA ;
Thomas, G .
SCIENCE, 1998, 279 (5351) :707-710
[38]   Biochemical and molecular mechanisms regulating apoptosis [J].
Saini, KS ;
Walker, NI .
MOLECULAR AND CELLULAR BIOCHEMISTRY, 1998, 178 (1-2) :9-25
[39]   Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B [J].
Stephens, L ;
Anderson, K ;
Stokoe, D ;
Erdjument-Bromage, H ;
Painter, GF ;
Holmes, AB ;
Gaffney, PRJ ;
Reese, CB ;
McCormick, F ;
Tempst, P ;
Coadwell, J ;
Hawkins, PT .
SCIENCE, 1998, 279 (5351) :710-714
[40]   Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B [J].
Stokoe, D ;
Stephens, LR ;
Copeland, T ;
Gaffney, PRJ ;
Reese, CB ;
Painter, GF ;
Holmes, AB ;
McCormick, F ;
Hawkins, PT .
SCIENCE, 1997, 277 (5325) :567-570