PHD3 inhibits cell proliferation through hydroxylation of PAX2 at proline 9  

作　　者：Jie Lun Yuxin Wang Qiang Gao Yu Wang Hongwei Zhang Jing Fang 

机构地区：[1]Cancer Institute,the Affiliated Hospital of Qingdao University,School of Basic Medicine of Qingdao University,Qingdao 266061,China [2]Shanghai Institute of Nutrition and Health,Chinese Academy of Sciences,Shanghai 200031,China [3]Shandong Provincial Maternal and Child Health Care Hospital,Jinan 250014,China

出　　处：《Acta Biochimica et Biophysica Sinica》2022年第5期708-715,共8页生物化学与生物物理学报（英文版）

基　　金：supported by the grants from Shandong Natural Science Foundation(No.ZR2020MH206);Ministry of Science and Technology of China(No.2020YFA0803301);National Natural Science Foundation of China(Nos.31470769 and 82073061).

摘　　要：The oncoprotein transcription factor paired box 2(PAX2)is aberrantly expressed in cancers,but the underlying mechanism remains elusive.Prolyl hydroxylase 3(PHD3)hydroxylates the proline residue of HIFα,mediating HIFαdegradation.The von Hippel-Lindau protein(pVHL)is an E3 ligase which mediates ubiquitination and degradation of hydroxylated HIFα.PHD3 and pVHL are found to inhibit the expression of PAX2,however,the molecular mechanism is unclear.Here we demonstrate that PHD3 hydroxylates PAX2 at proline 9,which is required for pVHL to mediate PAX2 ubiquitination and degradation.Overexpression of PHD3 enhances prolyl hydroxylation,ubiquitination and degradation of PAX2 with little effect on those of PAX2(P9A).PHD3 does not influence PAX2 expression in VHL-null cells.pVHL binds to PAX2 and enhances PAX2 ubiquitination and degradation.However,pVHL does not bind with PAX2(P9A)and cannot enhance its ubiquitination and degradation.Our results suggest that proline 9 hydroxylation is a prerequisite for PAX2 degradation by pVHL.Functional studies indicate that introduction of PAX2 into PAX2-null COS-7 cells promotes cell proliferation,which is suppressed by co-expression of PHD3 but not by hydroxylase-deficient PHD3(H196A).PHD3 inhibits PAX2-induced,but not PAX2(P9A)-induced proliferation of COS7 cells.These results suggest that PHD3 hydroxylates PAX2,followed by pVHL-mediated PAX2 ubiquitination and degradation.This study also suggests that PHD3 inhibits cell proliferation through downregulating PAX2.

关 键 词：PHD3 PAX2 PVHL prolyl hydroxylation cell proliferation 

分 类 号：R730[医药卫生—肿瘤]