Regulation of cyclin expression and cell cycle progression in breast epithelial cells by the helix-loop-helix protein Id1

Abstract

The helix-loop-helix protein Id1 has been implicated in regulating mammary epithelial cell proliferation and differentiation but the underlying molecular mechanisms are not well characterized. Under low serum conditions, ectopic expression of Id1, but not Id2, allowed continued proliferation of immortalized mammary epithelial cells and breast cancer cells. Conversely, downregulation of Id1 impaired proliferation. The effects of short interfering RNA (siRNA)-mediated downregulation of Id1 were the same as those following downregulation of c-Myc: decreased expression of cyclins D1 and E, reduced phosphorylation of pRb at Ser780 (a site targeted by cyclin D1-Cdk4) and reduced cyclin E-Cdk2 activity. Decreased cyclin D1 expression was an early response to Id1 antisense oligonucleotide treatment. Inhibition of c-Myc function by siRNA, antisense oligonucleotides or a dominant repressor resulted in downregulation of Id1, while ectopic expression of c-Myc resulted in rapid induction of Id1, suggesting that Id1 may be downstream of c-Myc. These data indicate that in mammary epithelial cells, Id1 has cell cycle regulatory functions that are similar to those of c-Myc, and suggest that cyclin D1 may be involved in Id1 regulation of cell cycle progression.