Regulation of PAI-1 gene expression during adipogenesis.
Obesity is characterized by elevated levels of circulating plasminogen activator inhibitor-1 (PAI-1), which contribute towards the development of secondary disorders such as type 2 diabetes mellitus and cardiovascular complications. This increase in plasma PAI-1 levels is attributed to an increase in PAI-1 derived from adipose tissue. This study shows that adipose tissue evolved into a major PAI-1 producing organ by gaining capacity during adipocyte differentiation to respond to inducers of PAI-1 transcription. This is mediated by a decrease in E2F1 protein levels, an increase in pRB levels and a decrease in pRB phosphorylation, all leading to a decrease in levels of free E2F, a known transcriptional repressor of PAI-1. Depletion of E2F1-3 was sufficient for inducers such as insulin to potently induce PAI-1 gene expression in pre-adipocytes. Conversely, forced release of pRB-bound endogenous E2F using cell-penetrating peptides can suppress PAI-1 gene expression in adipocytes. This study describes the novel paradigm of cellular differentiation-associated increase in PAI-1 gene expression which is mediated by a decrease in repressor activity, and describes a way of desensitising terminally differentiated cells to PAI-1 inducing agents by restoring endogenous repressor activity.
Venugopal
Joshi
J
Friedrich Miescher Institute for Biomedical Research, Novartis Research Foundation, Maulbeerstrasse 66, Basel, Switzerland.
Hanashiro
Kazuhiko
K
Nagamine
Yoshikuni
Y
D016475:3T3 Cells; D050156:Adipogenesis / Q000502:physiology*; D000818:Animals; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D050684:E2F Transcription Factors; D010455:Peptides; D017395:Plasminogen Activator Inhibitor 1; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D015842:Serine Proteinase Inhibitors