Effect of proline analogues on activity of human prolyl hydroxylase and the regulation of HIF signal transduction pathway.

Hypoxia inducible factor 1 (HIF-1) plays a pivotal role in cellular responses to hypoxia. Prolyl hydroxylase 3 (PHD3) degrades HIF-1α under normoxic conditions through the hydroxylation of HIF-1α for proteolysis. Inhibiting PHD3 activity is crucial for up-regulating HIF-1α, thereby acting as a poten...

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Autores principales:	Xiaoyan Ma, Xiaoxin Wang, Jing Cao, Zhirong Geng, Zhilin Wang
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/548a5cd5ca144cd6a6e1f2bae89c5ab3
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spelling	oai:doaj.org-article:548a5cd5ca144cd6a6e1f2bae89c5ab32021-11-18T08:21:52ZEffect of proline analogues on activity of human prolyl hydroxylase and the regulation of HIF signal transduction pathway.1932-620310.1371/journal.pone.0095692https://doaj.org/article/548a5cd5ca144cd6a6e1f2bae89c5ab32014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24755992/?tool=EBIhttps://doaj.org/toc/1932-6203Hypoxia inducible factor 1 (HIF-1) plays a pivotal role in cellular responses to hypoxia. Prolyl hydroxylase 3 (PHD3) degrades HIF-1α under normoxic conditions through the hydroxylation of HIF-1α for proteolysis. Inhibiting PHD3 activity is crucial for up-regulating HIF-1α, thereby acting as a potential target for treating hypoxia-related diseases. In this study, two proline analogues (PA1 and PA2) were screened as PHD3 inhibitors with apparent EC50 values of 1.53 and 3.17 µM respectively, indicating good inhibition potency. Nine proteins, significantly regulated by PA1, were identified using 2-DE coupled with MALDI-TOF/TOF MS. Pyruvate kinase isozymes M1/M2 (PKM) and alpha-enolase 1 (ENO1), which are key modulators of glycolysis, are directly regulated by HIF-1α. Moreover, VEGF, a signal protein stimulating angiogenesis, was strongly promoted by PA1. Our findings suggest that PA1 stabilized HIF-1α as well as up-regulated glycolysis and angiogenesis proteins. Herein, for the first time, we systematically studied proline analogue PA1 as a PHD3 inhibitor, which provides innovative evidence for the treatment of HIF-related diseases.Xiaoyan MaXiaoxin WangJing CaoZhirong GengZhilin WangPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 4, p e95692 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Xiaoyan Ma Xiaoxin Wang Jing Cao Zhirong Geng Zhilin Wang Effect of proline analogues on activity of human prolyl hydroxylase and the regulation of HIF signal transduction pathway.
description	Hypoxia inducible factor 1 (HIF-1) plays a pivotal role in cellular responses to hypoxia. Prolyl hydroxylase 3 (PHD3) degrades HIF-1α under normoxic conditions through the hydroxylation of HIF-1α for proteolysis. Inhibiting PHD3 activity is crucial for up-regulating HIF-1α, thereby acting as a potential target for treating hypoxia-related diseases. In this study, two proline analogues (PA1 and PA2) were screened as PHD3 inhibitors with apparent EC50 values of 1.53 and 3.17 µM respectively, indicating good inhibition potency. Nine proteins, significantly regulated by PA1, were identified using 2-DE coupled with MALDI-TOF/TOF MS. Pyruvate kinase isozymes M1/M2 (PKM) and alpha-enolase 1 (ENO1), which are key modulators of glycolysis, are directly regulated by HIF-1α. Moreover, VEGF, a signal protein stimulating angiogenesis, was strongly promoted by PA1. Our findings suggest that PA1 stabilized HIF-1α as well as up-regulated glycolysis and angiogenesis proteins. Herein, for the first time, we systematically studied proline analogue PA1 as a PHD3 inhibitor, which provides innovative evidence for the treatment of HIF-related diseases.
format	article
author	Xiaoyan Ma Xiaoxin Wang Jing Cao Zhirong Geng Zhilin Wang
author_facet	Xiaoyan Ma Xiaoxin Wang Jing Cao Zhirong Geng Zhilin Wang
author_sort	Xiaoyan Ma
title	Effect of proline analogues on activity of human prolyl hydroxylase and the regulation of HIF signal transduction pathway.
title_short	Effect of proline analogues on activity of human prolyl hydroxylase and the regulation of HIF signal transduction pathway.
title_full	Effect of proline analogues on activity of human prolyl hydroxylase and the regulation of HIF signal transduction pathway.
title_fullStr	Effect of proline analogues on activity of human prolyl hydroxylase and the regulation of HIF signal transduction pathway.
title_full_unstemmed	Effect of proline analogues on activity of human prolyl hydroxylase and the regulation of HIF signal transduction pathway.
title_sort	effect of proline analogues on activity of human prolyl hydroxylase and the regulation of hif signal transduction pathway.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/548a5cd5ca144cd6a6e1f2bae89c5ab3
work_keys_str_mv	AT xiaoyanma effectofprolineanaloguesonactivityofhumanprolylhydroxylaseandtheregulationofhifsignaltransductionpathway AT xiaoxinwang effectofprolineanaloguesonactivityofhumanprolylhydroxylaseandtheregulationofhifsignaltransductionpathway AT jingcao effectofprolineanaloguesonactivityofhumanprolylhydroxylaseandtheregulationofhifsignaltransductionpathway AT zhironggeng effectofprolineanaloguesonactivityofhumanprolylhydroxylaseandtheregulationofhifsignaltransductionpathway AT zhilinwang effectofprolineanaloguesonactivityofhumanprolylhydroxylaseandtheregulationofhifsignaltransductionpathway
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Effect of proline analogues on activity of human prolyl hydroxylase and the regulation of HIF signal transduction pathway.

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