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J Mol Cell Cardiol. 2014 Jul;72:28-38. doi: 10.1016/j.yjmcc.2014.02.007. Epub 2014 Feb 20.

PKA turnover by the REGγ-proteasome modulates FoxO1 cellular activity and VEGF-induced angiogenesis.

Author information

1
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.
2
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.
3
Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
4
Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China.
5
Department of Medicine, Dan L. Duncan Cancer Center Division of Biostatistics, Baylor College of Medicine, Houston, TX, USA.
6
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.
7
Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Luzhou Medical College, Luzhou 646000, China.
8
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.
9
Department of Orthopaedic Oncology, Changzheng Hospital, The Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China. Electronic address: jianruxiao@163.com.
10
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.

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.

KEYWORDS:

Angiogenesis; E-Selectin; FoxO1; PKAca; REGγ; VCAM-1

PMID:
24560667
PMCID:
PMC4237316
DOI:
10.1016/j.yjmcc.2014.02.007
[Indexed for MEDLINE]
Free PMC Article

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