title: Insulin-like Growth Factor 1 Signaling Axis Meets p53 Genome Protection Pathways.
abstract: Clinical, epidemiological, and experimental evidence indicate that the insulin-like growth factors (IGFs) are important mediators in the biochemical chain of events that lead from a phenotypically normal to a neoplastic cell. The IGF1 receptor (IGF1R), which mediates the biological actions of IGF1 and IGF2, exhibits potent pro-survival and antiapoptotic activities. The IGF1R is highly expressed in most types of cancer and is regarded as a promising therapeutic target in oncology. p53 is a transcription factor with tumor suppressor activity that is usually activated in response to DNA damage and other forms of cellular stress. On the basis of its protective activities, p53 is commonly regarded as the guardian of the genome. We provide evidence that the IGF signaling axis and p53 genome protection pathways are tightly interconnected. Wild-type, but not mutant, p53 suppresses IGF1R gene transcription, leading to abrogation of the IGF signaling network, with ensuing cell cycle arrest. Gain-of-function, or loss-of-function, mutations of p53 in tumor cells may disrupt its inhibitory activity, thus generating oncogenic molecules capable of transactivating the IGF1R gene. The interplay between the IGF1 and p53 pathways is also of major relevance in terms of metabolic regulation, including glucose transport and glycolysis. A better understanding of the complex physical and functional interactions between these important signaling pathways will have major basic and translational relevance.
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Yoran Institute for Human Genome Research, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Haim
authors.initials: H
authors.lastname: Werner
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University , Tel Aviv , Israel.
authors.forename: Rive
authors.initials: R
authors.lastname: Sarfstein
authors.affiliation: Diabetes and Metabolism Clinical Research Center, Rambam Health Care Center , Haifa , Israel.
authors.forename: Derek
authors.initials: D
authors.lastname: LeRoith
authors.affiliation: Department of Obstetrics and Gynecology, Hillel Yaffe Medical Center , Hadera , Israel.
authors.forename: Ilan
authors.initials: I
authors.lastname: Bruchim
keywords: BRCA1; IGF1 receptor; genome protection; insulin-like growth factor 1; p53; transcription regulation; tumor suppressors