p53, the Cellular Gatekeeper for Growth and Division

[D.ap]

Volume 88, Issue 3, p323–331, 7 February 1997

Review
p53, the Cellular Gatekeeper for Growth and Division

Arnold J Levine
correspondence

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The p53 gene and its protein product have become the center of intensive study ever since it became clear that slightly more than 50% of human cancers contain mutations in this gene. An extensive database (Hollstein et al. 1994

) catalogs these mutations in more than 50 different cell and tissue types, although some types of cancers never appear to select for p53 mutations (Lutzker and Levine 1996

). The nature of these genetic changes in cancer cells is most commonly a missense mutation in one allele, producing a faulty protein that is then observed at high concentrations in these cells, followed by a reduction to homozygosity. More rarely, deletions or chain-termination mutations in the p53 gene indicate that the null phenotype predisposes to cancer, as has been observed in mice with a homozygous p53 null mutation (Donehower et al. 1992

). There have been some suggestions that the missense mutant producing a faulty p53 protein could contribute a “gain of function” phenotype (Dittmer et al. 1993

), but this remains to be substantiated by additional experimentation.

A study of the mutational spectra at the p53 locus in different tissue types indicates a strong role for diverse environmental mutagens, with a set of tissue preferences. In addition, there is strong selection for a subset of mutations localized predominantly in the DNA-binding domain of the protein. Several codons in this domain that are never observed in the p53 mutational spectra have been altered by site-specific mutagenesis, and in all cases these mutations have no phenotype and behave like the wild-type (Lin et al. 1995

). Thus, both selection and a strong set of environmental mutagens combine to produce mutations in the p53 gene in human cancers.



http://www.cell.com/cell/fulltext/S0092-8674(00)81871-1



Ann Diagn Pathol. 2000 Jun;4(3):135-42.

Alveolar soft part sarcoma: the role of prognostic markers.

Sanjuan X1, Sobel ME, Yang J, Merino MJ.

Author information

Abstract

Alveolar soft part sarcoma (ASPS) is a rare malignant neoplasm characterized by slow growth and indolent behavior. The role of proliferative markers and tumor suppressor genes is unknown in these tumors. To investigate their potential role in diagnosis and prognosis, we studied 13 cases of primary ASPS and 14 metastases and correlated them with clinicopathologic parameters. Immunohistochemistry was performed with anti-p53 and anti-Ki-67 antibodies. Polymerase chain reaction after tumor microdissection was performed to search for possible loss of heterozygosity in chromosomes 1p, 9p, 17q, 22q, and TP53 to identify possible changes that may clarify the histogenesis of these tumors. Four of five (80%) primary ASPS cases were positive for Ki-67 and all of them developed later metastases. One patient whose tumor did not stain for Ki-67 remained free of disease for 9 years. Eleven of 13 (85%) metastases were positive for Ki-67; however, there was no correlation with final outcome. All the primary ASPS cases analyzed for p53 yielded negative results, but two (15%) of 13 metastases were weakly positive. There was no correlation of these markers with prognosis or clinicopathologic parameters. No loss of heterozygosity was found except in one of nine (11%) informative metastases for D1S165 (at 1p36). Our preliminary data suggest that Ki-67-positive immunostaining may be a prognostic indicator for the development of metastases in ASPS.

PMID: 10919382 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov/pubmed/10919382

[D.ap]

The Ki-67 protein: from the known and the unknown
J Cell Physiol. 2000 Mar;182(3):311-22.

* The Ki-67 protein: from the known and the unknown.

Scholzen T1, Gerdes J.



Author information



Abstract

The expression of the human Ki-67 protein is strictly associated with cell proliferation. During interphase, the antigen can be exclusively detected within the nucleus, whereas in mitosis most of the protein is relocated to the surface of the chromosomes. The fact that the Ki-67 protein is present during all active phases of the cell cycle (G(1), S, G(2), and mitosis), but is absent from resting cells (G(0)), makes it an excellent marker for determining the so-called growth fraction of a given cell population. In the first part of this study, the term proliferation marker is discussed and examples of the applications of anti-Ki-67 protein antibodies in diagnostics of human tumors are given. The fraction of Ki-67-positive tumor cells (the Ki-67 labeling index) is often correlated with the clinical course of the disease. The best-studied examples in this context are carcinomas of the prostate and the breast. For these types of tumors, the prognostic value for survival and tumor recurrence has repeatedly been proven in uni- and multivariate analysis. The preparation of new monoclonal antibodies that react with the Ki-67 equivalent protein from rodents now extends the use of the Ki-67 protein as a proliferation marker to laboratory animals that are routinely used in basic research. The second part of this review focuses on the biology of the Ki-67 protein. Our current knowledge of the Ki-67 gene and protein structure, mRNA splicing, expression, and cellular localization during the cell-division cycle is summarized and discussed. Although the Ki-67 protein is well characterized on the molecular level and extensively used as a proliferation marker, the functional significance still remains unclear. There are indications, however, that Ki-67 protein expression is an absolute requirement for progression through the cell-division cycle.

Copyright 2000 Wiley-Liss, Inc.



http://www.ncbi.nlm.nih.gov/pubmed/10653597