title: Prolyl hydroxylase domain protein 3 targets Pax2 for destruction.
abstract: Prolyl hydroxylase domain proteins (PHDs) hydroxylate HIFα in the presence of oxygen, leading to HIFα proteasomal destruction. The PHDs family comprises PHD1, 2, and 3. Recent studies indicate that, in addition to HIFα, PHDs have other substrates. Paired box (Pax) 2, a transcription factor, was found aberrantly expressed in a variety of cancers. However, the underlying mechanisms remain unknown. Here we demonstrate that PHD3 is a negative regulator of expression of Pax2. We found that PHD3 bound to Pax2 and mediated Pax2 destruction directly. Inhibition of PHD3 hydroxylase activity led to upregulation of Pax2 protein but not mRNA level. We found that Pax2 protein was increased and PHD3 protein was decreased in colorectal cancer, and the increased Pax2 was associated with decreased PHD3. Our results suggest that PHD3 targets Pax2 for destruction. The findings may disclose a mechanism for the regulation of Pax2 expression in cancer cells.
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Yan
authors.forename: Shi
authors.initials: S
authors.lastname: Jiao
authors.forename: Hai-sheng
authors.initials: HS
authors.lastname: Zhang
authors.forename: Dan-dan
authors.initials: DD
authors.lastname: Lv
authors.forename: Jing
authors.initials: J
authors.lastname: Xue
authors.forename: Li
authors.initials: L
authors.lastname: Fan
authors.forename: Guo-hao
authors.initials: GH
authors.lastname: Wu
authors.forename: Jing
authors.initials: J
authors.lastname: Fang
mesh_terms: D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism*; D049308:Dioxygenases / Q000378:metabolism*; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D051762:PAX2 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D051762:PAX2 Transcription Factor; C497318:PAX2 protein, human; D049308:Dioxygenases; C488894:EGLN3 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases