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Induction of the growth inhibitor IGF-binding protein 3 by p53
L Buckbinder1, R Talbott, S Velasco-Miguel
1Department of Molecular Genetics, Oncology, Bristol-Myers Squibb Pharmaceutical Research Institute, New Jersey 08543-4000, USA.
Abstract:
Transcriptional activation of target genes represents an important component of the tumour-suppressor function of p53 and provides a functional link between p53 and various growth-regulatory processes, including cell cycle progression (p21/WAF1), DNA repair (GADD45) and apoptosis (bax). Here we use a differential cloning approach to identify the gene encoding insulin-like growth factor binding protein 3 (IGF-BP3) as a novel p53-regulated target gene. Induction of IGF-BP3 gene expression by wild-type but not mutant p53 is associated with enhanced secretion of an active form of IGF-BP3 capable of inhibiting mitogenic signalling by the insulin-like growth factor IGF-1. Our results indicate that IGF-BP3 may link p53 to potential novel autocrine/paracrine signalling pathways and to processes regulated by or dependent on IGF(s), such as cellular growth, transformation and survival.
Insights
The tumor suppressor p53 activates the insulin-like growth factor binding protein 3 (IGF-BP3) gene. This leads to inhibition of insulin-like growth factor 1 (IGF-1) signaling, impacting cell growth and survival.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Signaling
Background:
- The tumor suppressor p53 plays a crucial role in regulating cell growth, DNA repair, and apoptosis through transcriptional activation of target genes.
- p53's tumor-suppressor functions are linked to growth regulation, cell cycle progression (e.g., p21/WAF1), DNA repair (e.g., GADD45), and apoptosis (e.g., bax).
Purpose of the Study:
- To identify novel p53-regulated target genes.
- To investigate the functional link between p53 and insulin-like growth factor (IGF) signaling pathways.
Main Methods:
- Differential cloning approach to identify novel p53 target genes.
- Analysis of IGF-BP3 gene expression and protein secretion in response to wild-type and mutant p53.
- Assessment of the inhibitory activity of secreted IGF-BP3 on IGF-1 mitogenic signaling.
Main Results:
- Identified insulin-like growth factor binding protein 3 (IGF-BP3) as a novel p53-regulated target gene.
- Wild-type p53, but not mutant p53, induced IGF-BP3 gene expression.
- Induced IGF-BP3 was secreted in an active form capable of inhibiting insulin-like growth factor 1 (IGF-1) mitogenic signaling.
Conclusions:
- IGF-BP3 is a novel target gene of the tumor suppressor p53.
- p53-mediated induction of IGF-BP3 links p53 to IGF signaling pathways.
- This pathway may regulate cellular growth, transformation, and survival through autocrine/paracrine mechanisms.