p34SEI-1 inhibits doxorubicin-induced senescence through a pathway mediated by protein kinase C-delta and c-Jun-NH2-kinase 1 activation in human breast cancer MCF7 cells.
In this study, we describe a novel function of the p34(SEI-1) protein, which is both an oncogenic protein and a positive regulator of the cell cycle. The p34(SEI-1) protein was found to inhibit doxorubicin-induced senescence. We investigated the molecular mechanisms of the inhibitory effect of p34(SEI-1) on senescence. First, we found that the activation of protein kinase C-delta (PKC-delta), which is cleaved into a 38 kDa active form from a 78 kDa pro-form, induced after doxorubicin treatment, was inhibited by p34(SEI-1). Furthermore, p34(SEI-1) induced the ubiquitination of PKC-delta. Yet, there is no interaction between p34(SEI-1) and PKC-delta. We also found that the phosphorylation of c-Jun-NH(2)-kinase 1 (JNK1) induced after doxorubicin treatment was suppressed by p34(SEI-1), but not in JNK2. Consistently, pharmacologic or genetic inactivation of either PKC-delta or JNK1 was found to inhibit doxorubicin-induced senescence. In addition, the genetic inactivation of PKC-delta by PKC-delta small interfering RNA resulted in an inhibition of JNK1 activation, but PKC-delta expression was not inactivated by JNK1 small interfering RNA, implying that the activation of JNK1 could be dependently induced by PKC-delta. Therefore, p34(SEI-1) inhibits senescence by inducing PKC-delta ubiquitination and preventing PKC-delta-dependent phosphorylation of JNK1.
Lee
Sae Lo Oom
SL
Research Center for Women's Diseases, Division of Biological Sciences, Sookmyung Women's University, Seoul, Korea.
Hong
Seung-Woo
SW
Shin
Jae-Sik
JS
Kim
Jin Sun
JS
Ko
Seong-Gyu
SG
Hong
Nam-Joo
NJ
Kim
Dae Jin
DJ
Lee
Wang-Jae
WJ
Jin
Dong-Hoon
DH
Lee
Myeong-Sok
MS
D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002352:Carrier Proteins / Q000378:metabolism; D016922:Cellular Senescence / Q000187:drug effects*; D004317:Doxorubicin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D014162:Transfection; D044767:Ubiquitin-Protein Ligases
D002352:Carrier Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C402464:SERTAD1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D004317:Doxorubicin; C505879:TRIM41 protein, human; D044767:Ubiquitin-Protein Ligases; D051745:Protein Kinase C-delta; D048055:Mitogen-Activated Protein Kinase 8