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.

Abstract

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.

• Authors: Sae Lo Oom Lee, Seung-Woo Hong, Jae-Sik Shin, Jin Sun Kim, Seong-Gyu Ko, Nam-Joo Hong, Dae Jin Kim, Wang-Jae Lee, Dong-Hoon Jin, Myeong-Sok Lee
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 7 Issue 11 Pg. 1845-53 (Nov 2009) ISSN: 1557-3125 [Electronic] United States
• PMID: 19903772 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• Nuclear Proteins
• RNA, Small Interfering
• SERTAD1 protein, human
• Trans-Activators
• Transcription Factors
• Doxorubicin
• TRIM41 protein, human
• Ubiquitin-Protein Ligases
• Protein Kinase C-delta
• Mitogen-Activated Protein Kinase 8

Topics

• Breast Neoplasms (drug therapy, genetics, metabolism, pathology)
• Carrier Proteins (metabolism)
• Cellular Senescence (drug effects)
• Doxorubicin (antagonists & inhibitors, pharmacology)
• Enzyme Activation
• Female
• Humans
• Mitogen-Activated Protein Kinase 8 (metabolism)
• Nuclear Proteins (biosynthesis, genetics, metabolism)
• Phosphorylation
• Protein Kinase C-delta (genetics, metabolism)
• RNA, Small Interfering (administration & dosage, genetics)
• Trans-Activators (biosynthesis, genetics, metabolism)
• Transcription Factors
• Transfection
• Ubiquitin-Protein Ligases