Induction of the growth inhibitor IGF-binding protein 3 by p53

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.

Twenty years of p53 research: structural and functional aspects of the p53 protein

“…While induction of the p21 WAF1 gene has been shown not to be essential for p53-mediated apoptosis, p53 induces the expression of Fas/APO1 (Owen-Schaub et al, 1995), member of the death receptor family, BAX Selvakumaran et al, 1994;Miyashita and Reed, 1995;Han et al, 1996) the product of which can antagonize the anti-apoptotic activity of Bcl-2 (White, 1996) and IGF-BP3 (Buckbinder et al, 1995), which sequesters the cell survival factor insulin-like growth factor-1 (Baserga, 1994); the gene encoding the cathepsin-D protease (Wu et al, 1998) PAG608 which encodes a nuclear zinc ®nger protein (Israeli et al, 1997) and the human homolog of the Drosophila sina gene (Nemani et al, 1996). Recently a series of p53-induced genes (PIG genes) have been identi®ed that are predicted to encode proteins that could generate or respond to oxidative stress.…”

Downmodulation of bFGF-binding protein expression following restoration of p53 function

“…At day 4, the message was virtually undetectable. In contrast, no significant change was apparent in the RNA levels of MDM-2 (a protein that modulates p53 activity ), the antimitogenic factor IGF -BP3, ( an autocrine /growth regulator through its inhibition of the insulin growth factor pathway, which can be induced in cells after DNA damage, 54 ) or the antiangiogenic factor TSP -1. Both IGF -BP3 and TSP -1 have been implicated in the bystander effect in other systems.…”

“…On the basis of published sequences for bFGF -BP 25 and IGF -BP3, 54 we prepared pairs of oligonucleotide primers for RT-PCR of these genes. RT-PCR of the human -actin gene was used as internal control.…”

Human smooth muscle α-actin gene is a transcriptional target of the p53 tumor suppressor protein

“…A number of transcriptional targets of p53 have been identi®ed. These include, mdm-2, gadd45, p21/WAF, cyclin G, IGF-BP3, bax, etc., Barak et al, 1993;Kastan et al, 1992;El-Deiry et al, 1993;Okamoto and Beach, 1994;Buckbinder et al, 1995;Miyashita and Reed, 1995). The proteins encoded by these target genes participate mainly in either cycle control or in the apoptotic pathway.…”