Author(s): Liao, Y (Liao, Y.); Wei, Y (Wei, Y.); Zhou, X (Zhou, X.); Yang, JY (Yang, J-Y); Dai, C (Dai, C.); Chen, YJ (Chen, Y-J); Agarwal, NK (Agarwal, N. K.); Sarbassov, D (Sarbassov, D.); Shi, D (Shi, D.); Yu, D (Yu, D.); Hung, MC (Hung, M-C)
Title: Peptidyl-prolyl cis/trans isomerase Pin1 is critical for the regulation of PKB/Akt stability and activation phosphorylation
Source: ONCOGENE, 28 (26): 2436-2445 JUL 2009 Language: English
Document Type: Article
Author Keywords: PKB/Akt; Pin1; peptidyl-prolyl cis/trans isomerase; breast cancer KeyWords Plus: PROTEIN-KINASE-B; FORKHEAD TRANSCRIPTION FACTORS;
BREAST-CANCER; AKT; PATHWAY; AKT/PKB; DISEASE; OVEREXPRESSION;
TUMORIGENESIS; EXPRESSION
Abstract: The serine/threonine protein kinase B (PKB, also known as Akt) plays a pivotal role in diverse cellular functions. Elevated expression of activated Akt has been detected in a wide variety of human cancers; however, the mechanism of Akt protein stability regulation remains unclear. In this study, we showed a strong correlation between the expression levels of an oncogenic peptidyl-prolyl cis/trans isomerase Pin1 and levels of Akt phosphorylation at S473 in multiple cancer types (P<0.0001). Akt-pS473 status combined with Pin1 expression levels predicted a poorer prognosis than did either one alone in patients with breast cancer (P = 0.0052). We further showed that Pin1 regulated Akt stability and phosphorylation on S473 through the phosphorylated Thr-Pro motifs of Akt. These motifs are conserved evolutionary and are required for the maintenance of Akt stability and its interaction with Pin1. In addition, repressing Pin1 expression through either homologue Pin1 knockout or small interfering RNA- mediated knockingdown compromised its ability to protect Akt from degradation. Our results show how Akt protein stability is regulated by the peptidyl-prolyl cis/trans isomerase Pin1 and highlight the importance of this oncogenic network in human disease pathogenesis. Oncogene (2009) 28, 2436-2445; doi: 10.1038/onc.2009.98; published online 18 May 2009
Addresses: [Liao, Y.; Wei, Y.; Zhou, X.; Yang, J-Y; Chen, Y-J; Agarwal, N. K.; Sarbassov, D.;
Yu, D.; Hung, M-C] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA; [Liao, Y.; Dai, C.] Univ Texas MD Anderson Canc Ctr, Dept Mol Pathol, Houston, TX 77030 USA; [Zhou, X.; Shi, D.] Fudan Univ, Canc Hosp, Dept Pathol, Shanghai 200433, Peoples R China; [Chen, Y-J; Hung, M-C] China Med Univ & Hosp, Ctr Mol Med, Taichung, Taiwan; [Chen, Y-J; Hung, M-C] China Med Univ & Hosp, Grad Inst Canc Biol, Taichung, Taiwan; [Hung, M-C] Asia Univ, Taichung, Taiwan
Reprint Address: Hung, MC, Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, 1515 Holcombe Blvd, Houston, TX 77030 USA.
E-mail Address: [email protected]; [email protected]
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Publisher: NATURE PUBLISHING GROUP
Publisher Address: MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND ISSN: 0950-9232
DOI: 10.1038/onc.2009.98
29-char Source Abbrev.: ONCOGENE ISO Source Abbrev.: Oncogene Source Item Page Count: 10
Subject Category: Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics &
Heredity
ISI Document Delivery No.: 465QH
