Protein kinase Cδ regulates apoptosis via activation of STAT1

被引:47
作者
DeVries, TA [1 ]
Kalkofen, RL [1 ]
Matassa, AA [1 ]
Reyland, ME [1 ]
机构
[1] Univ Colorado, Hlth Sci Ctr, Dept Craniofacial Biol, Sch Dent, Denver, CO 80262 USA
关键词
D O I
10.1074/jbc.M407448200
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
Protein kinase Cdelta(PKCdelta) is required for mitochondria-dependent apoptosis; however, little is known about downstream effectors of PKCdelta in apoptotic cells. Here we show that activation of STAT1 is an early response to DNA damage and that STAT1 activation requires PKCdelta. Treatment of HeLa cells with etoposide results in phosphorylation of STAT1 on Ser(727) and the association of STAT1 with PKCdelta. Etoposide increases transcription from STAT1-dependent reporter constructs. Increased transcription, as well as STAT1 Ser(727) phosphorylation, can be blocked by inhibition or depletion of PKCdelta. To ask if STAT1 is required for PKCdelta-mediated apoptosis, we utilized U3A STAT1-deficient cells. Induction of apoptosis by PKCdelta is suppressed in U3A cells but can be rescued by co-transfection with STAT1alpha but not STAT1 mutated at Ser(727). Nuclear accumulation of STAT1, phospho-Ser(727) STAT1, and PKCdelta are detectable 30-60 min after treatment with etoposide. Nuclear localization is necessary for apoptosis, since a nuclear localization mutant of PKCdelta does not induce apoptosis in U3A cells reconstituted with STAT1alpha, and a nuclear localization mutant of STAT1 does not support PKCdelta-induced apoptosis in U3A cells. Our data identify STAT1 as a downstream target of PKCdelta and suggest that PKCdelta may regulate apoptosis by activation of STAT1 target genes.
引用
收藏
页码:45603 / 45612
页数:10
相关论文
共 58 条
[1]   A road map for those who don't know JAK-STAT [J].
Aaronson, DS ;
Horvath, CM .
SCIENCE, 2002, 296 (5573) :1653-1655
[2]   Ways of dying: multiple pathways to apoptosis [J].
Adams, JM .
GENES & DEVELOPMENT, 2003, 17 (20) :2481-2495
[3]   Stat1-dependent, p53-independent expression of p21waf1 modulates oxysterol-induced apoptosis [J].
Agrawal, S ;
Agarwal, ML ;
Chatterjee-Kishore, M ;
Stark, GR ;
Chisolm, GM .
MOLECULAR AND CELLULAR BIOLOGY, 2002, 22 (07) :1981-1992
[4]   Involvement of protein kinase C-δ in DNA damage-induced apoptosis [J].
Basu, A ;
Woolard, MD ;
Johnson, CL .
CELL DEATH AND DIFFERENTIATION, 2001, 8 (09) :899-908
[5]   Inactivation of DNA-dependent protein kinase by protein kinase Cδ:: Implications for apoptosis [J].
Bharti, A ;
Kraeft, SK ;
Gounder, M ;
Pandey, P ;
Jin, SF ;
Yuan, ZM ;
Lees-Miller, SP ;
Weichselbaum, R ;
Weaver, D ;
Chen, LB ;
Kufe, D ;
Kharbanda, S .
MOLECULAR AND CELLULAR BIOLOGY, 1998, 18 (11) :6719-6728
[6]   Tyrosine phosphorylation of protein kinase Cδ is essential for its apoptotic effect in response to etoposide [J].
Blass, M ;
Kronfeld, I ;
Kazimirsky, G ;
Blumberg, PM ;
Brodie, C .
MOLECULAR AND CELLULAR BIOLOGY, 2002, 22 (01) :182-195
[7]   Regulation of cell apoptosis by protein kinase c δ [J].
Brodie, C ;
Blumberg, PM .
APOPTOSIS, 2003, 8 (01) :19-27
[8]   Stable suppression of tumorigenicity by virus-mediated RNA interference [J].
Brummelkamp, TR ;
Bernards, R ;
Agami, R .
CANCER CELL, 2002, 2 (03) :243-247
[9]   Association of STATs with relatives and friends [J].
Chatterjee-Kishore, M ;
van den Akker, F ;
Stark, GR .
TRENDS IN CELL BIOLOGY, 2000, 10 (03) :106-111
[10]   PKC-δ is an apoptotic lamin kinase [J].
Cross, T ;
Griffiths, G ;
Deacon, E ;
Sallis, R ;
Gough, M ;
Watters, D ;
Lord, JM .
ONCOGENE, 2000, 19 (19) :2331-2337