title: p27 suppresses arsenite-induced Hsp27/Hsp70 expression through inhibiting JNK2/c-Jun- and HSF-1-dependent pathways.
abstract: 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.
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987, USA.
authors.forename: Jinyi
authors.initials: J
authors.lastname: Liu
authors.forename: Dongyun
authors.initials: D
authors.lastname: Zhang
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Mi
authors.forename: Qing
authors.initials: Q
authors.lastname: Xia
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Yu
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Zuo
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.forename: Xuewei
authors.initials: X
authors.lastname: Zhao
authors.forename: Jia
authors.initials: J
authors.lastname: Cao
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
authors.forename: Angela
authors.initials: A
authors.lastname: Zhu
authors.forename: Wancai
authors.initials: W
authors.lastname: Yang
authors.forename: Xianglin
authors.initials: X
authors.lastname: Shi
authors.forename: Jingxia
authors.initials: J
authors.lastname: Li
authors.forename: Chuanshu
authors.initials: C
authors.lastname: Huang
mesh_terms: 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
chemical_list: 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