Abstract
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.
Highlights
:j:To whom correspondence should be addressed: Dept. of Cell Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030
Mutations that abolished IRNF-I and IRNF-II binding greatly reduced the expression of the hlR gene, indicating that both factors are important for the human insulin receptor (hIR) gene expression (Lee et al, 1992)
To investi gate whether retinoblastoma gene product (Rb) regulates hI R gene expression, a construct containing t he hIR pr omoter fused to a bacterial CAT reporter was co-trans fecte d in to Hep G2 cells in t he presence or absence of Rb
Summary
Vol 270, No 35, Issue of September I, pp. 20525-20529, 1995 Printed in U.S.A. Stimulation of Human Insulin Receptor Gene Expression by Retinoblastoma Gene Product*. Multiple cis-acting elements have been defined to be important for the transcriptional regulation of the human insulin receptor (hIR) gene expression. We have previously demonstrated that these GA and GC boxes bind Spl with high affinity and are responsible for Ela activation of hIR promoter activity. Spl is a GC box-specific binding protein, which activates the transcription of many viral and cellular genes, including the 8V40, epidermal growth factor receptor, insulin-like growth factor binding protein-2, and transforming growth factor-Sf gene as well as the hlR gene (Lee et al, 1992; Dynan and Tjian, 1983; Xu et al, 1993; Boisclair et al, 1993; Kim et al, 1991).
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