Library Subscription: Guest
Begell Digital Portal Begell Digital Library eBooks Journals References & Proceedings Research Collections
Critical Reviews™ in Oncogenesis
SJR: 0.631 SNIP: 0.503 CiteScore™: 2

ISSN Print: 0893-9675
ISSN Online: 2162-6448

Critical Reviews™ in Oncogenesis

DOI: 10.1615/CritRevOncog.v5.i1.20
pages 23-58

Posttranslational Regulation of p53 Tumor Suppressor Protein Function

Steve A. Maxwell
Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, The University of Texas − M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030
Jack A. Roth
Department of Thoracic and Cardiovascular Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas


Alteration of the p53 gene by deletion and mutation is the most common denominator yet identified among human cancers (Hollstein et al., 1991; Caron de Fromental and Soussi, 1992). The involvement of the p53 gene in such a broad scope of human cancers warrants further investigation into its mechanism of action in regulating cell growth. The wild-type p53 protein restricts cell growth in the G, phase of the cell cycle by regulating the transcription of genes and possibly, by influencing DNA replication. Elucidating the cell growth restriction of p53 will require identification and characterization of the genes whose expression is regulated by p53 and the proteins that interact with p53 to regulate its DNA-binding and transactivation functions. A model for the regulation of p53 biochemical function is proposed that extends further and builds on the conformational hypothesis for regulation of p53 function hypothesized by Milner (1991) and Ullrich et al. (1992a). The conformational hypothesis of regulation of p53 function states that the conformation of p53 determines whether it expresses growth-suppressing or growth-promoting biological activity. Mutations observed in human cancer lock p53 in a growth-promoting conformation. We expand the conformational hypothesis in a regulatory model that includes binding proteins, kinases/phosphatases, redox modifier proteins, and homo/hetero-oligomerization, which modulate the tertiary structure of the protein. Different conformational modes of p53 interact differently with initiation complexes at gene promoters and at origins of DNA replication. Each form of p53, depending on its interaction with proteins and gene transcription-initiation complexes, will mediate distinct biological effects on cells ranging from growth suppression to growth promotion. Furthermore, depending on its conformational state, p53 can repress or activate other transcription factors thus indirectly affecting gene regulation. We propose that each cell and tissue type expresses unique quantities and types of p53-binding proteins and modifying enzymes that regulate the interaction of p53 with promoters of genes necessary for control of growth of a specific cell or tissue. It is anticipated that defects in the expression of p53 regulatory proteins are involved in a portion of those tumors expressing normal p53. Defects in the p53 biochemical pathway may thus be even more prevalent in human cancers than is now realized.

Articles with similar content:

Transcription Regulator Yin-Yang 1: From Silence to Cancer
Critical Reviews™ in Oncogenesis, Vol.16, 2011, issue 3-4
Weidong Zhu, Hermes Garban, Samuel Y. Olson
Tumor Metastasis to Brain: Role of Endothelial Cells, Neurotrophins, and Paracrine Growth Factors
Critical Reviews™ in Oncogenesis, Vol.5, 1994, issue 5
Philip Cavanaugh, Motowo Nakajima, Garth L. Nicolson, Dario Marchetti, Libin Jia, David G. Menter, Jun-ichi Hamada, John Herrmann, Zhong Yun
Oncogene-lnitiated Aberrant Signaling Engenders the Metastatic Phenotype: Synergistic Transcription Factor Interactions are Targets for Cancer Therapy
Critical Reviews™ in Oncogenesis, Vol.7, 1996, issue 3-4
David T. Denhardt
Acquisition of MHC-Specific Receptors on Murine Natural Killer Cells
Critical Reviews™ in Immunology, Vol.23, 2003, issue 4
Brian T. Wilhelm, Dixie L. Mager, Fumio Takei, Linnea L. Veinotte
Cell-Context Dependent TCF/LEF Expression and Function: Alternative Tales of Repression, De-Repression and Activation Potentials
Critical Reviews™ in Eukaryotic Gene Expression, Vol.21, 2011, issue 3
Catherine D. Mao, Stephen W. Byers