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The insulin-like growth factors (IGF1 and IGF2) are a family of mitogenic peptides with important roles in diverse aspects of body function ( 1). Modern biological research is aimed at dissecting physiological and pathological processes at defined levels of regulation and tackling biological questions in a comprehensive and integrated manner. Disruption of this finely tuned genetic program may lead to a pathological phenotype, including tumor formation. The processes of growth, development, and cell death are tightly regulated by multiple cellular and secreted factors that, in a highly orchestrated fashion, control the stage- and tissue-specific expression of a wide array of genes. The Insulin-Like Growth Factor Network: Ligands, Receptors, and Binding Proteins A better understanding of the complex physical and functional interactions between these important signaling pathways will have major basic and translational relevance. The interplay between the IGF1 and p53 pathways is also of major relevance in terms of metabolic regulation, including glucose transport and glycolysis. 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. Wild-type, but not mutant, p53 suppresses IGF1R gene transcription, leading to abrogation of the IGF signaling network, with ensuing cell cycle arrest. We provide evidence that the IGF signaling axis and p53 genome protection pathways are tightly interconnected. On the basis of its protective activities, p53 is commonly regarded as the guardian of the genome. p53 is a transcription factor with tumor suppressor activity that is usually activated in response to DNA damage and other forms of cellular stress. The IGF1R is highly expressed in most types of cancer and is regarded as a promising therapeutic target in oncology. The IGF1 receptor (IGF1R), which mediates the biological actions of IGF1 and IGF2, exhibits potent pro-survival and antiapoptotic activities. 4Department of Obstetrics and Gynecology, Hillel Yaffe Medical Center, Hadera, IsraelĬlinical, 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.3Diabetes and Metabolism Clinical Research Center, Rambam Health Care Center, Haifa, Israel.2Yoran Institute for Human Genome Research, Tel Aviv University, Tel Aviv, Israel.1Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.IGF1 and p53 Collaborate in Regulation of Metabolism.Can p53 Status Predict Responsiveness to IGF1R-Directed Targeted Therapies?.Regulation of the IGF Axis by Genome Protection Genes: A Common Theme in Cell Biology.Convergence of Tumor Suppressor p53 and IGF1 Signaling Pathways.Regulation of IGF1R Gene Expression by p53 Homologs.Differential Regulation of IGF1R Gene Expression by Wild-Type and Mutant p53.p53: A Key Player in Genome Integrity Protection.Transcriptional and Epigenetic Regulation of the IGF1R Gene.The IGF1R: A Potent Cell Survival Mediator.IGFs Play Key Roles in Homeostasis Regulation: Physiological and Pathological Aspects.
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The Insulin-Like Growth Factor Network: Ligands, Receptors, and Binding Proteins.The editor and reviewers' affiliations are the latest provided on their Loop research profiles and may not reflect their situation at the time of review. Swiss Federal Institute of Technology Lausanne, Switzerland