Multiple cis-acting elements have been defined to be important for the transcriptional regulation of the human insulin receptor (hIR) gene expression. We report here that one of these elements also mediated the stimulation of hIR promoter activity by the retinoblastoma gene product (Rb). The cis-element responsible for Rb stimulation was localized to the GA and GC boxes situated between -643 to -607 of the hIR gene. We have previously demonstrated that these GA and GC boxes bind Sp1 with high affinity and are responsible for E1a activation of hIR promoter activity. Mutation of these sequences completely abolished Rb-dependent enhancement of hIR promoter activity. In addition, we localized three regions in the N-terminal domain of Rb to be involved in stimulation of hIR promoter activity. Our results represent one of the first studies to demonstrate a functional importance assigned to the multiple phosphorylation sites in the N terminus of Rb. Finally, the mechanism by which Rb activates the hIR promoter are presented.

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