title: The prolyl isomerase Pin1 enhances HER-2 expression and cellular transformation via its interaction with mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1.
abstract: The HER-2 oncogene, a member of the erythroblastosis oncogene B (ERBB)-like oncogene family, has been shown to be amplified in many types of cancer, including breast cancer. However, the molecular mechanism of HER-2 overexpression is not completely understood. The phosphorylation of proteins on the serine or threonine residues that immediately precede proline (pSer/Thr-Pro) is specifically catalyzed by the prolyl isomerase Pin1 and is a key signaling mechanism in cell proliferation and transformation. Here, we found that Pin1 interacts with mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) protein kinase 1, resulting in the induction of HER-2 expression. Pin1(-/-) mouse embryonic fibroblasts exhibited a decrease in epidermal growth factor (EGF)-induced MEK1/2 phosphorylation compared with Pin1(+/+) mouse embryonic fibroblast. In addition, a knockdown of Pin1 resulted in the inhibition of MEK1/2 phosphorylation induced by EGF in MCF-7 cells. Furthermore, PD98059, a specific inhibitor of MEK1/2, and Juglone, a potent Pin1 inhibitor, markedly suppressed the expression of activator protein-2alpha and the HER-2 promoter activity induced by EGF or 12-O-tetradecanoylphorbol-13-acetate in MCF-7 cells. Importantly, these inhibitors inhibited the neoplastic cell transformation induced by EGF in Pin1-overexpressing JB6 Cl41 cells, which showed enhanced cellular formation compared with the control cells. Therefore, Juglone and PD98059 inhibited the colony formation of MCF-7 breast cancer cells in soft agar. These results indicate that Pin1 amplifies EGF signaling in breast cancer cells through its interaction with MEK1 and then enhances HER-2 expression, suggesting that Pin1 plays an important role in the overexpression of HER-2 through Pin1-MEK1-activator protein-2alpha signaling in breast cancer.
authors.affiliation: BK21 Project Team, College of Pharmacy, Chosun University, Gwangju, Republic of Korea.
authors.forename: Prem
authors.initials: P
authors.lastname: Khanal
authors.forename: Gwang Mo
authors.initials: GM
authors.lastname: Namgoong
authors.forename: Bong Seok
authors.initials: BS
authors.lastname: Kang
authors.forename: Eun-Rhan
authors.initials: ER
authors.lastname: Woo
authors.forename: Hong Seok
authors.initials: HS
authors.lastname: Choi
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000378:metabolism* / Q000502:physiology; D048370:MAP Kinase Kinase 2 / Q000378:metabolism / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism / Q000502:physiology; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D011485:Protein Binding / Q000502:physiology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology
chemical_list: D004815:Epidermal Growth Factor; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D048052:Mitogen-Activated Protein Kinase 3; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase; D018719:Erb-b2 Receptor Tyrosine Kinases; C482128:MAP2K2 protein, human; C508053:ERBB2 protein, human; C482125:MAP2K1 protein, human; C000606846:PIN1 protein, human; C000606850:Pin1 protein, mouse