The helix-loop-helix protein Id-1 delays onset of replicative senescence in human endothelial cells

Id proteins are negative regulators of basic helix-loop-helix transcription factors, which are critical for expression of genes associated with cellular differentiation. Previous studies have shown that overexpression of Id-1 delays cellular senescence in several cell types, including fibroblasts, mammary epithelial cells, and keratinocytes. Although previous studies have demonstrated the expression of Id-1 in endothelium, the regulation of Id-1 has not been studied in these cells. In this report, a retroviral vector was used to overexpress Id-1 in human endothelial cells. Sustained expression of Id-1 resulted in a 2- to 3-fold increase in the total number of population doublings (replicative capacity) of the cells compared with vector-treated controls, which correlated with low levels of p16, p21, and p27 expression. The cells, however, were not immortalized and did eventually undergo senescence despite elevated Id-1 levels. Senescence was characterized by a dramatic increase in p16, but not p21 and p27. Under these experimental conditions, telomerase activity was not detected and the telomeres became progressively shorter with time. These results demonstrate the importance of Id-1 in endothelial cell proliferation and indicate that Id-1 represses p16 expression, resulting in delayed senescence. These findings may have implications in the development of endothelial cell-derived tumors.