title: Roles of TP53 in determining therapeutic sensitivity, growth, cellular senescence, invasion and metastasis.
abstract: TP53 is a critical tumor suppressor gene that regulates cell cycle progression, apoptosis, cellular senescence and many other properties critical for control of normal cellular growth and death. Due to the pleiotropic effects that TP53 has on gene expression and cellular physiology, mutations at this tumor suppressor gene result in diverse physiological effects. T53 mutations are frequently detected in numerous cancers. The expression of TP53 can be induced by various agents used to treat cancer patients such as chemotherapeutic drugs and ionizing radiation. Radiation will induce Ataxia telangiectasia mutated (ATM) and other kinases that results in the phosphorylation and activation of TP53. TP53 is also negatively regulated by other mechanisms, such as ubiquitination by ligases such as MDM2. While TP53 has been documented to control the expression of many "classical" genes (e.g., p21Cip-1, PUMA, Bax) by transcriptional mechanisms for quite some time, more recently TP53 has been shown to regulate microRNA (miR) gene expression. Different miRs can promote oncogenesis (oncomiR) whereas others act to inhibit tumor progression (tumor suppressor miRs). Targeted therapies to stabilize TP53 have been developed by various approaches, MDM2/MDM4 inhibitors have been developed to stabilize TP53 in TP53-wild type (WT) tumors. In addition, small molecules have been isolated that will reactivate certain mutant TP53s. Both of these types of inhibitors are in clinical trials. Understanding the actions of TP53 may yield novel approaches to suppress cancer, aging and other health problems.
authors: Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA. Electronic address: mccubreyj@ecu.edu.
authors: James A
authors: JA
authors: McCubrey
authors: Department of Comparative Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors: Kvin
authors: K
authors: Lertpiriyapong
authors: Department of Surgery, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors: Timothy L
authors: TL
authors: Fitzgerald
authors: Department of Biomedical and Neuromotor Sciences, Università di Bologna, Bologna, Italy.
authors: Alberto M
authors: AM
authors: Martelli
authors: Department of Biomedical and Neuromotor Sciences, Università di Bologna, Bologna, Italy.
authors: Lucio
authors: L
authors: Cocco
authors: Department of Animal Molecular Physiology, Institute of Experimental Biology, Wroclaw University, Wroclaw, Poland.
authors: Dariusz
authors: D
authors: Rakus
authors: Department of Animal Molecular Physiology, Institute of Experimental Biology, Wroclaw University, Wroclaw, Poland.
authors: Agnieszka
authors: A
authors: Gizak
authors: Department of Bio-Medical Sciences, University of Catania, Catania, Italy.
authors: Massimo
authors: M
authors: Libra
authors: Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare "Alberto Monroy", Palermo, Italy.
authors: Melchiorre
authors: M
authors: Cervello
authors: Biomedical Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy.
authors: Guiseppe
authors: G
authors: Montalto
authors: Department of Internal Medicine, Hematology/Oncology Section, Brody School of Medicine at East Carolina University, Greenville, NC, USA.
authors: Li V
authors: LV
authors: Yang
authors: Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
authors: Stephen L
authors: SL
authors: Abrams
authors: Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
authors: Linda S
authors: LS
authors: Steelman
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001372:Aza Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects* / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D001372:Aza Compounds; C494826:BAX protein, human; C438378:BBC3 protein, human; D019086:Bridged Bicyclo Compounds, Heterocyclic; D050759:Cyclin-Dependent Kinase Inhibitor p21; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C451219:2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one
keywords: Cellular senescence; Invasion; MDM2; Metastasis; Nutlin-3 chemosensitivity; TP53; miRs