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

  title={Induction of the growth inhibitor IGF-binding protein 3 by p53},
  author={Leonard Buckbinder and Randy L Talbott and Susana Velasco-Miguel and Ivone M. Takenaka and Barbara Faha and Bernd R. Seizinger and Nikolai Kley},
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)1á¤-3, DNA repair (GADD45)4 and apoptosis (bax)5. 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… 
Insulin-like growth factor binding protein-2 is a novel mediator of p53 inhibition of insulin-like growth factor signaling
It is shown that IGFBP-2 is also a p53 target, and p53 effects on the IGF axis are more complex than previously appreciated, and overall transform the axis from IGF-mediated mitogenesis to growth inhibition and apoptosis.
The p53/IGF-1 receptor axis in the regulation of programmed cell death
Elucidation of novel pathways downstream of p53 have established a link between this important tumor suppressor gene and the insulin-like growth factor-1 receptor (IGF-1r), highlighting a novel pathway whereby p53 may regulate apoptosis in tumor cells.
P53 and IGFBP-3: apoptosis and cancer protection.
  • A. Grimberg
  • Biology, Medicine
    Molecular genetics and metabolism
  • 2000
Induction by p53 of the insulin-like growth factor binding protein (IGFBP)-3 constitutes a new means of cross-talk between the p53 and IGF axes, and suggests that the ultimate function of IGFBP-3 may be to serve a protective role against the potentially carcinogenic effects of growth hormone and IGF-I.
Wild-type and mutant p53 differentially regulate transcription of the insulin-like growth factor I receptor gene.
It is suggested that wild-type p53 has the potential to suppress the IGF-I-R promoter in the postmitotic, fully differentiated cell, thus resulting in low levels of receptor gene expression in adult tissues.
Insulin-like Growth Factor 1 Signaling Axis Meets p53 Genome Protection Pathways
Evidence is provided that the IGF signaling axis and p53 genome protection pathways are tightly interconnected and of major relevance in terms of metabolic regulation, including glucose transport and glycolysis.
The anti-tumor mechanisms of p53 through the regulation of expression and glycosylation of insulin-like growth factor binding protein-3
The anti-tumor activity of IGFBP-3 was shown to improve the stabilization of IGFbp-3 through the increment of glycosylation of IGF BP-3 by p53, suggesting that the combined gene therapy of p53 and IGFBP -3 may appropriate treatment of cancer.
p53-Dependent and p53-independent induction of insulin-like growth factor binding protein-3 by deoxyribonucleic acid damage and hypoxia.
It is established that IGF BP-3 induction under hypoxic conditions is independent of p53 in tumor cell lines derived form multiple tissue types, suggesting IGFBP-3 plays a role in the physiologic protection against aberrant cell growth.
Signalling pathways involved in antiproliferative effects of IGFBP-3: a review
Findings all point to a complex intracellular mode of action of IGFBP-3, which will need to be better understood if anti-cancer treatments are to take advantage of the antiproliferative activity of IGF BP-3.
Differential activation of target cellular promoters by p53 mutants with impaired apoptotic function.
Results suggest that activation of cell cycle arrest genes by p53 can be separated from activation of genes with a role in mediating the p53 apoptotic response, and may depend on which group of p53-responsive genes become transcriptionally activated.
Differential activation of the IGF binding protein-3 promoter by butyrate in prostate cancer cells.
It is demonstrated that NaB significantly up-regulates IGFBP-3 mRNA and protein levels in PC-3 and LNCaP prostate cancer cells; and novel butyrate- responsive elements lacking consensus Sp1 sites are used in L NCaP cells.


Gene regulation by temperature-sensitive p53 mutants: identification of p53 response genes.
Results show that p53 activates the expression of numerous response genes and suggest that multiple effectors may play a role in mediating cellular functions of p53.
Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo.
It is demonstrated that a temperature-sensitive p53 induces temperature-dependent decreases in the expression of the apoptosis-suppressing gene bcl-2 in the murine leukemia cell M1, while simultaneously stimulating increases in theexpression of bax, a gene which encodes a dominant-inhibitor of the Bcl-1 protein.
Regulation of the Sequence-specific DNA Binding Function of p53 by Protein Kinase C and Protein Phosphatases (*)
Evidence is provided that phosphorylation of serine 378 within the carboxyl-terminal negative regulatory domain of the human p53 protein by protein kinase C correlates with loss of PAb421 reactivity and a concomitant activation of sequence-specific DNA binding.
Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen.
Gadd45 was found to bind to PCNA, a normal component of Cdk complexes and a protein involved in DNA replication and repair, establishing GADD45 as a link between the p53-dependent cell cycle checkpoint and DNA repair.
p21 is a universal inhibitor of cyclin kinases
It is found that over expression of p21 inhibits the activity of each member of the cyclin/CDK family, and this results indicate that p21 may be a universal inhibitor of cyclin kinases.
Enhanced expression of an insulin growth factor-like binding protein (mac25) in senescent human mammary epithelial cells and induced expression with retinoic acid.
It is found that mac25 accumulates in senescent cells and is up-regulated in normal, growing mammary epithelial cells by all-trans-retinoic acid or the synthetic retinoid fenretinide, suggesting a tumor-suppressor role.
Biological effects of prostate specific antigen as an insulin-like growth factor binding protein-3 protease.
It is concluded that PSA decreases the affinity of IGF BP-3 for IGF and can potentiate IGF action in the presence of inhibitory IGFBP-3, which may contribute to normal and malignant prostate growth.