title: Regulation of p53: intricate loops and delicate balances.
abstract: The p53 tumor suppressor protein provides a major anti-cancer defense mechanism, as underscored by the fact that the p53 gene is the most frequent target for genetic alterations in human cancer. Recent work has led to the realization that p53 lies at the hub of a very complex network of signaling pathways, which integrate a variety of intracellular and extracellular inputs. Part of this network consists of an array of autoregulatory feedback loops, where p53 exhibits very intricate interactions with other proteins known to play important roles in the determination of cell fate. We discuss two such loops, one involving the beta catenin protein and the other centering on the Akt/protein kinase B. In both cases, the central module is the interplay between p53 and the murine double minute 2 (Mdm2) protein, which inactivates p53 and targets it for rapid proteolysis. Whereas deregulated beta catenin can lead to Mdm2 inactivation and p53 accumulation, active p53 can promote the degradation and downregulation of beta catenin. Similarly, Akt can block p53 activation by potentiating Mdm2, whereas activated p53 can tune down Akt in several different ways. In each case, the actual output of the loop is determined by the delicate balance between the opposing effects of its different components. Often, this balance is dictated by additional signaling processes that occur simultaneously within the same cell. Genetic alterations characteristic of cancer are capable of severely distorting this balance, thereby overriding the tumor suppressor effects of p53 in a manner that facilitates neoplastic conversion.
authors.affiliation: Department of Molecular Cell Biology, The Weizmann Institute of Science, P.O. Box 26, Rehovot, Israel. moshe.oren@weizmann.ac.il
authors.forename: Moshe
authors.initials: M
authors.lastname: Oren
authors.forename: Alexander
authors.initials: A
authors.lastname: Damalas
authors.forename: Tanya
authors.initials: T
authors.lastname: Gottlieb
authors.forename: Dan
authors.initials: D
authors.lastname: Michael
authors.forename: Jan
authors.initials: J
authors.lastname: Taplick
authors.forename: Juan Fernando Martinez
authors.initials: JF
authors.lastname: Leal
authors.forename: Ruth
authors.initials: R
authors.lastname: Maya
authors.forename: Miri
authors.initials: M
authors.lastname: Moas
authors.forename: Rony
authors.initials: R
authors.lastname: Seger
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Taya
authors.forename: Avri
authors.initials: A
authors.lastname: Ben-Ze'ev
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002453:Cell Cycle; D002470:Cell Survival; D003598:Cytoskeletal Proteins / Q000378:metabolism; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D016158:Genes, p53; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051736:Proto-Oncogene Proteins c-mdm2; D015534:Trans-Activators / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt