title: PKA turnover by the REGγ-proteasome modulates FoxO1 cellular activity and VEGF-induced angiogenesis.
abstract: The REGγ-proteasome serves as a short-cut for the destruction of certain intact mammalian proteins in the absence of ubiquitin- and ATP. The biological roles of the proteasome activator REGγ are not completely understood. Here we demonstrate that REGγ controls degradation of protein kinase A catalytic subunit-α (PKAca) both in primary human umbilical vein endothelial cells (HUVECs) and mouse embryonic fibroblast cells (MEFs). Accumulation of PKAca in REGγ-deficient HUVECs or MEFs results in phosphorylation and nuclear exclusion of the transcription factor FoxO1, indicating that REGγ is involved in preserving FoxO1 transcriptional activity. Consequently, VEGF-induced expression of the FoxO1 responsive genes, VCAM-1 and E-Selectin, was tightly controlled by REGγ in a PKA dependent manner. Functionally, REGγ is crucial for the migration of HUVECs. REGγ(-/-) mice display compromised VEGF-instigated neovascularization in cornea and aortic ring models. Implanted matrigel plugs containing VEGF in REGγ(-/-) mice induced fewer capillaries than in REGγ(+/+) littermates. Taken together, our study identifies REGγ as a novel angiogenic factor that plays an important role in VEGF-induced expression of VCAM-1 and E-Selectin by antagonizing PKA signaling. Identification of the REGγ-PKA-FoxO1 pathway in endothelial cells (ECs) provides another potential target for therapeutic intervention in vascular diseases.
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China; Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China; Department of Hematology, Guangdong No. 2 Provincial People's Hospital, No.1 Shiliugang Rd, Guangzhou, Guangdong 510317, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Liu
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China; Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
authors.forename: Li
authors.initials: L
authors.lastname: Lai
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China; Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
authors.forename: Qiuhong
authors.initials: Q
authors.lastname: Zuo
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China; Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
authors.forename: Fujun
authors.initials: F
authors.lastname: Dai
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China; Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wu
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China; Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China; Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
authors.forename: Qingxia
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Liu
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China; Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China; Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
authors.forename: Qingxiang
authors.initials: Q
authors.lastname: Lin
authors.affiliation: Department of Medicine, Dan L. Duncan Cancer Center Division of Biostatistics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.affiliation: Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Myra Grace
authors.initials: MG
authors.lastname: Costello
authors.affiliation: Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Shixia
authors.initials: S
authors.lastname: Huang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China; Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
authors.forename: Caifeng
authors.initials: C
authors.lastname: Jia
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China; Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
authors.forename: Lujian
authors.initials: L
authors.lastname: Liao
authors.affiliation: The James Hogg Research Centre for Cardiovascular and Pulmonary Research, University of British Columbia-St. Paul's Hospital, 1081 Burrard St., Vancouver, British Columbia V6Z 1Y6, Canada.
authors.forename: Honglin
authors.initials: H
authors.lastname: Luo
authors.affiliation: Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Luzhou Medical College, Luzhou 646000, China.
authors.forename: Junjiang
authors.initials: J
authors.lastname: Fu
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China; Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China; Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China. Electronic address: yizhengfang@gmail.com.
authors.forename: Zhengfang
authors.initials: Z
authors.lastname: Yi
authors.affiliation: Department of Orthopaedic Oncology, Changzheng Hospital, The Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China. Electronic address: jianruxiao@163.com.
authors.forename: Jianru
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Orthopaedic Oncology, Changzheng Hospital, The Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China; Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China. Electronic address: xiaotaol@bcm.edu.
authors.forename: Xiaotao
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001324:Autoantigens / Q000235:genetics* / Q000378:metabolism; D002465:Cell Movement; D003315:Cornea / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000235:genetics* / Q000378:metabolism; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D018919:Neovascularization, Physiologic; D061251:Primary Cell Culture; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D059748:Proteolysis; D015398:Signal Transduction; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
chemical_list: D001324:Autoantigens; D019040:E-Selectin; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; C099558:Ki antigen; D019010:Vascular Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; C463959:protein kinase A Calpha; D046988:Proteasome Endopeptidase Complex
keywords: Angiogenesis; E-Selectin; FoxO1; PKAca; REGγ; VCAM-1