p27 suppresses arsenite-induced Hsp27/Hsp70 expression through inhibiting JNK2/c-Jun- and HSF-1-dependent pathways.
p27 is an atypical tumor suppressor that can regulate the activity of cyclin-dependent kinases and G(0)-to-S phase transitions. More recent studies reveal that p27 may also exhibit its tumor-suppressive function through regulating many other essential cellular events. However, the molecular mechanisms underlying these anticancer effects of p27 are largely unknown. In this study, we found that depletion of p27 expression by either gene knock-out or knockdown approaches resulted in up-regulation of both Hsp27 and Hsp70 expression at mRNA- and promoter-derived transcription as well as protein levels upon arsenite exposure, indicating that p27 provides a negative signal for regulating the expression of Hsp27 and Hsp70. Consistently, arsenite-induced activation of JNK2/c-Jun and HSF-1 pathways was also markedly elevated in p27 knock-out (p27(-/-)) and knockdown (p27 shRNA) cells. Moreover, interference with the expression or function of JNK2, c-Jun, and HSF-1, but not JNK1, led to dramatic inhibition of arsenite-induced Hsp27 and Hsp70 expression. Collectively, our results demonstrate that p27 suppresses Hsp27 and Hsp70 expression at the transcriptional level specifically through JNK2/c-Jun- and HSF-1-dependent pathways upon arsenite exposure, which provides additional important molecular mechanisms for the tumor-suppressive function of p27.
Liu
Jinyi
J
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987, USA.
Zhang
Dongyun
D
Mi
Xiaoyi
X
Xia
Qing
Q
Yu
Yonghui
Y
Zuo
Zhenghong
Z
Guo
Wei
W
Zhao
Xuewei
X
Cao
Jia
J
Yang
Qing
Q
Zhu
Angela
A
Yang
Wancai
W
Shi
Xianglin
X
Li
Jingxia
J
Huang
Chuanshu
C
D000818:Animals; D018053:Arsenites / Q000494:pharmacology*; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005347:Fibroblasts; D055551:HSP27 Heat-Shock Proteins / Q000032:analysis / Q000235:genetics*; D018840:HSP70 Heat-Shock Proteins / Q000032:analysis / Q000235:genetics*; D000076249:Heat Shock Transcription Factors; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction / Q000187:drug effects; D013723:Teratogens; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D025521:Tumor Suppressor Proteins
D018053:Arsenites; D004268:DNA-Binding Proteins; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D012333:RNA, Messenger; D013723:Teratogens; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D048056:Mitogen-Activated Protein Kinase 9; D048031:JNK Mitogen-Activated Protein Kinases; C015001:arsenite