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Peptidyl Prolyl Isomerase PIN1 Directly Binds to and Stabilizes Hypoxia-Inducible Factor-1α

Cited 18 time in Web of Science Cited 24 time in Scopus
Authors
Han, Hyeong-Jun; Kwon, Nayoung; Choi, Min-A; Jung, Kyung Oh; Piao, Juan-Yu; Ngo, Hoang Kieu Chi; Kim, Su-Jung; Kim, Do-Hee; Chung, June-Key; Cha, Young-Nam; Youn, Hyewon; Choi, Bu Young; Min, Sang-Hyun; Surh, Young-Joon
Issue Date
2016-01
Citation
PLoS ONE, Vol.11 No.1, p. e0147038
Abstract
Peptidyl prolyl isomerase (PIN1) regulates the functional activity of a subset of phosphoproteins through binding to phosphorylated Ser/Thr-Pro motifs and subsequently isomerization of the phosphorylated bonds. Interestingly, PIN1 is overexpressed in many types of malignancies including breast, prostate, lung and colon cancers. However, its oncogenic functions have not been fully elucidated. Here, we report that PIN1 directly interacts with hypoxia-inducible factor (HIF)-1 alpha in human colon cancer (HCT116) cells. PIN1 binding to HIF-1 alpha occurred in a phosphorylation-dependent manner. We also found that PIN1 interacted with HIF-1 alpha at both exogenous and endogenous levels. Notably, PIN1 binding stabilized the HIF-1 alpha protein, given that their levels were significantly increased under hypoxic conditions. The stabilization of HIF-1 alpha resulted in increased transcriptional activity, consequently upregulating expression of vascular endothelial growth factor, a major contributor to angiogenesis. Silencing of PIN1 or pharmacologic inhibition of its activity abrogated the angiogenesis. By utilizing a bioluminescence imaging technique, we were able to demonstrate that PIN1 inhibition dramatically reduced the tumor volume in a subcutaneous mouse xenograft model and angiogenesis as well as hypoxia-induced transcriptional activity of HIF-1 alpha. These results suggest that PIN1 interacting with HIF-1 alpha is a potential cancer chemopreventive and therapeutic target.
ISSN
1932-6203
URI
https://hdl.handle.net/10371/172935
DOI
https://doi.org/10.1371/journal.pone.0147038
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Graduate School of Convergence Science and Technology (융합과학기술대학원)Dept. of Molecular and Biopharmaceutical Sciences (분자의학 및 바이오제약학과)Journal Papers (저널논문_분자의학 및 바이오제약학과)
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