title: A new tumour suppression mechanism by p27Kip1: EGFR down-regulation mediated by JNK/c-Jun pathway inhibition.
abstract: p27Kip1 is a potent inhibitor of cyclin-dependent kinases that drive G1-to-S cell-cycle transition. Reduced p27Kip1 expression is prevalent in a wide range of human tumours; however, the exact mechanism(s) of p27Kip1-mediated tumour suppression remains obscure. In the present study, we identified a close inverse relationship between p27Kip1 and EGFR (epidermal growth factor receptor) expression: the parental T24 human bladder cancer cells had high p27Kip1 expression but low EGFR expression and, in striking contrast, the metastatic derivative of T24 (T24T) had low p27Kip1 expression but high EGFR expression. This relationship was also found in various human cancer tissues, and was not only just correlative but also causal; depletion of p27Kip1 in MEF (mouse embryonic fibroblast) cells resulted in markedly elevated EGFR expression, a result reproducible with an Egfr promoter-luciferase reporter in both T24 and MEF cells, suggesting transcriptional repression of EGFR by p27Kip1. Indeed, p27Kip1 was found to regulate EGFR expression via the JNK (c-Jun N-terminal kinase)/c-Jun transcription factor: p27Kip1 deficiency activated JNK/c-Jun, whereas inhibition of JNK/c-Jun by dominant-negative mutants dramatically repressed Egfr transcription. Furthermore, the proximal promoter of the Egfr gene was crucial for its transcription, where the recruiting activity of c-Jun was much greater in p27Kip1-/- cells than in p27Kip1+/+ cells. Introduction of GFP-p27Kip1 into T24T cells suppressed JNK/c-Jun activation, EGFR expression and anchorage-independent growth. The results of the present study demonstrate that p27Kip1 suppresses JNK/c-Jun activation and EGFR expression in MEFs and human bladder cancer cells, and the results obtained are consistent with those from human cancer specimens. The present study provides new insights into p27Kip1 suppression of cancer cell growth, migration and metastasis.
authors.forename: Yong
authors.initials: Y
authors.lastname: Fang
authors.affiliation: ‡Department of Pathology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: †Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, U.S.A.
authors.forename: Yulei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: †Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, U.S.A.
authors.forename: Yan
authors.initials: Y
authors.lastname: Meng
authors.affiliation: †Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, U.S.A.
authors.forename: Junlan
authors.initials: J
authors.lastname: Zhu
authors.affiliation: †Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, U.S.A.
authors.forename: Honglei
authors.initials: H
authors.lastname: Jin
authors.affiliation: †Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, U.S.A.
authors.forename: Jingxia
authors.initials: J
authors.lastname: Li
authors.affiliation: †Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, U.S.A.
authors.forename: Dongyun
authors.initials: D
authors.lastname: Zhang
authors.affiliation: †Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, U.S.A.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Yu
authors.forename: Xue-Ru
authors.initials: XR
authors.lastname: Wu
authors.affiliation: †Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, U.S.A.
authors.forename: Chuanshu
authors.initials: C
authors.lastname: Huang
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D055786:Gene Knockout Techniques; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D015398:Signal Transduction; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: C436291:CDKN1B protein, human; D016755:Proto-Oncogene Proteins c-jun; D050760:Cyclin-Dependent Kinase Inhibitor p27; C512478:EGFR protein, human; D066246:ErbB Receptors; D048031:JNK Mitogen-Activated Protein Kinases