Phosphorylation at tyrosine 114 of Proliferating Cell Nuclear Antigen (PCNA) is required for adipogenesis in response to high fat diet |
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| Authors: | Yuan-Hung Lo Po-Chun Ho Min-Shan Chen Eric Hugo Nira Ben-Jonathan Shao-Chun Wang |
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| Institution: | 1. Robert Stempel College of Public Health and Social Work, Department of Nutrition and Dietetics, Florida International University, Miami, FL 33199, USA;2. School of Biological and Population Health Sciences and Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA;1. Clinical Research Unit, Khoo Teck Puat Hospital, 90 Yishun Central, Singapore 768828, Singapore;2. Diabetes Centre, Khoo Teck Puat Hospital, 90 Yishun Central, Singapore 768828, Singapore;3. National Healthcare Group Polyclinics, 3 Fusionopolis Link, Nexus@one-north, South Tower, # 05-10, Singapore 138543, Singapore;1. Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow, G61 1BD, UK;2. Bone Marrow Transplant Unit, Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow, G12 OYN, UK;3. Paul O''Gorman Leukaemia Research Centre, College of Medical, Veterinary and Life Sciences, Institute of Cancer Sciences, University of Glasgow, 21 Shelley Road, Gartnavel General Hospital, Glasgow, G12 0ZD, UK;1. Department of Applied Science, National Hsinchu University of Education, Hsinchu 30014, Taiwan, ROC;2. Department of Cardiac Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA;3. Material and Chemical Research Laboratories, Industrial Technology Research Institute, Hsinchu 31040, Taiwan, ROC |
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| Abstract: | Clonal proliferation is an obligatory component of adipogenesis. Although several cell cycle regulators are known to participate in the transition between pre-adipocyte proliferation and terminal adipocyte differentiation, how the core DNA synthesis machinery is coordinately regulated in adipogenesis remains elusive. PCNA (Proliferating Cell Nuclear Antigen) is an indispensable component for DNA synthesis during proliferation. Here we show that PCNA is subject to phosphorylation at the highly conserved tyrosine residue 114 (Y114). Replacing the Y114 residue with phenylalanine (Y114F), which is structurally similar to tyrosine but cannot be phosphorylated, does not affect normal animal development. However, when challenged with high fat diet, mice carrying homozygous Y114F alleles (PCNAF/F) are resistant to adipose tissue enlargement in comparison to wild-type (WT) mice. Mouse embryonic fibroblasts (MEFs) harboring WT or Y114F mutant PCNA proliferate at similar rates. However, when subjected to adipogenesis induction in culture, PCNAF/F MEFs are not able to re-enter the cell cycle and fail to form mature adipocytes, while WT MEFs undergo mitotic clonal expansion in response to the adipogenic stimulation, accompanied by enhanced Y114 phosphorylation of PCNA, and differentiate to mature adipocytes. Consistent with the function of Y114 phosphorylation in clonal proliferation in adipogenesis, fat tissues isolated from WT mice contain significantly more adipocytes than those isolated from PCNAF/F mice. This study identifies a critical role for PCNA in adipose tissue development, and for the first time identifies a role of the core DNA replication machinery at the interface between proliferation and differentiation. |
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