Author
Michael A. Tainsky
Other affiliations: University of Texas MD Anderson Cancer Center, Howard Hughes Medical Institute
Bio: Michael A. Tainsky is an academic researcher from Wayne State University. The author has contributed to research in topics: Cancer & Transfection. The author has an hindex of 50, co-authored 140 publications receiving 14860 citations. Previous affiliations of Michael A. Tainsky include University of Texas MD Anderson Cancer Center & Howard Hughes Medical Institute.
Topics: Cancer, Transfection, Gene, Gene expression, Cell culture
Papers published on a yearly basis
Papers
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TL;DR: Germ line p53 mutations have been detected in all five LFS families analyzed and can now be examined in additional families with LFS, and in other cancer patients and families with clinical features that might be attributed to the mutation.
Abstract: Familial cancer syndromes have helped to define the role of tumor suppressor genes in the development of cancer. The dominantly inherited Li-Fraumeni syndrome (LFS) is of particular interest because of the diversity of childhood and adult tumors that occur in affected individuals. The rarity and high mortality of LFS precluded formal linkage analysis. The alternative approach was to select the most plausible candidate gene. The tumor suppressor gene, p53, was studied because of previous indications that this gene is inactivated in the sporadic (nonfamilial) forms of most cancers that are associated with LFS. Germ line p53 mutations have been detected in all five LFS families analyzed. These mutations do not produce amounts of mutant p53 protein expected to exert a trans-dominant loss of function effect on wild-type p53 protein. The frequency of germ line p53 mutations can now be examined in additional families with LFS, and in other cancer patients and families with clinical features that might be attributed to the mutation.
3,662 citations
TL;DR: Transfection assays indicate that, in fibroblasts, wild-type p53 inhibits angiogenesis through regulation of TSP-1 synthesis.
Abstract: As normal cells progress toward malignancy, they must switch to an angiogenic phenotype to attract the nourishing vasculature that they depend on for their growth. In cultured fibroblasts from Li-Fraumeni patients, this switch was found to coincide with loss of the wild-type allele of the p53 tumor suppressor gene and to be the result of reduced expression of thrombospondin-1 (TSP-1), a potent inhibitor of angiogenesis. Transfection assays revealed that p53 can stimulate the endogenous TSP-1 gene and positively regulate TSP-1 promoter sequences. These data indicate that, in fibroblasts, wild-type p53 inhibits angiogenesis through regulation of TSP-1 synthesis.
1,482 citations
TL;DR: It is shown that the wild-type p53 allele is lost when fibroblasts from patients with the Li-Fraumeni syndrome are passaged in vitro, and p53 contributes to a metabolically regulated G1 check-point, and they provide a model for understanding how abnormal cell cycle progression leads to the genetic rearrangements involved in tumor progression.
1,090 citations
TL;DR: Molecular cloning of the transforming gene from a chemically transformed human osteosarcoma-derived cell line enables the gene to be mapped to chromosome 7 (7p11.4–7qter) and by direct hybridization to be shown to be unrelated to known oncogenes.
Abstract: Molecular cloning of the transforming gene from a chemically transformed human osteosarcoma-derived cell line enables the gene to be mapped to chromosome 7 (7p11.4-7qter) and by this criterion and by direct hybridization to be shown to be unrelated to known oncogenes.
951 citations
Journal Article•
TL;DR: It is concluded that the loss of p53 by itself is insufficient to confer immortality on a cell, but does confer a growth advantage, confirming that the absence of p 53 promotes genomic instability, which in turn may result in genetic alterations which directly produce immortality.
Abstract: Fibroblast cultures were derived from mouse embryos containing either one (p53+/-) or two (p53-/-) inactivated p53 alleles and compared to normal embryo fibroblasts for a number of growth parameters. Early passage p53-deficient embryo fibroblasts (p53-/-) divided faster than normal embryo fibroblasts, achieved higher confluent densities, and had a higher fraction of division-competent cells under conditions of low cell density. Flow cytometry studies of early passage embryo fibroblasts showed that the percent of p53-deficient cells in G0/G1 was lower than in normal cells, consistent with the argument that p53 mediates a G1 block. When p53-deficient and normal cells were passaged for long periods of time, the homozygote (p53-/-) fibroblasts grew at a high rate for over 50 passages and never entered a non-growing senescent phase characteristic of the heterozygote (p53+/-) and normal (p53+/+) cells. The p53-deficient fibroblasts were genetically unstable during passaging, with the p53-/- cells showing a high degree of aneuploidy and the p53+/- cells displaying a moderate level of chromosomal abnormalities by passage 25. Surprisingly, the heterozygote cells lost their single wild type allele very early during culturing and in spite of this loss most heterozygote lines entered into senescence. We conclude that the loss of p53 by itself is insufficient to confer immortality on a cell, but does confer a growth advantage. Taken together, the findings confirm that the absence of p53 promotes genomic instability, which in turn may result in genetic alterations which directly produce immortality.
503 citations
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TL;DR: This work has been supported by the Department of the Army and the National Institutes of Health, and the author acknowledges the support and encouragement of the National Cancer Institute.
28,811 citations
TL;DR: A gene is identified, named WAF1, whose induction was associated with wild-type but not mutant p53 gene expression in a human brain tumor cell line and that could be an important mediator of p53-dependent tumor growth suppression.
8,339 citations
TL;DR: The p53 mutational spectrum differs among cancers of the colon, lung, esophagus, breast, liver, brain, reticuloendothelial tissues, and hemopoietic tissues as mentioned in this paper.
Abstract: Mutations in the evolutionarily conserved codons of the p53 tumor suppressor gene are common in diverse types of human cancer. The p53 mutational spectrum differs among cancers of the colon, lung, esophagus, breast, liver, brain, reticuloendothelial tissues, and hemopoietic tissues. Analysis of these mutations can provide clues to the etiology of these diverse tumors and to the function of specific regions of p53. Transitions predominate in colon, brain, and lymphoid malignancies, whereas G:C to T:A transversions are the most frequent substitutions observed in cancers of the lung and liver. Mutations at A:T base pairs are seen more frequently in esophageal carcinomas than in other solid tumors. Most transitions in colorectal carcinomas, brain tumors, leukemias, and lymphomas are at CpG dinucleotide mutational hot spots. G to T transversions in lung, breast, and esophageal carcinomas are dispersed among numerous codons. In liver tumors in persons from geographic areas in which both aflatoxin B1 and hepatitis B virus are cancer risk factors, most mutations are at one nucleotide pair of codon 249. These differences may reflect the etiological contributions of both exogenous and endogenous factors to human carcinogenesis.
8,063 citations
TL;DR: Think of the switch to the angiogenic phenotype as a net balance of positive and negative regulators of blood vessel growth, which may dictate whether a primary tumour grows rapidly or slowly and whether metastases grow at all.
Abstract: Recent discoveries of endogenous negative regulators of angiogenesis, thrombospondin, angiostatin and glioma-derived angiogenesis inhibitory factor, all associated with neovascularized tumours, suggest a new paradigm of tumorigenesis. It is now helpful to think of the switch to the angiogenic phenotype as a net balance of positive and negative regulators of blood vessel growth. The extent to which the negative regulators are decreased during this switch may dictate whether a primary tumour grows rapidly or slowly and whether metastases grow at all.
7,916 citations
TL;DR: The work from the authors' laboratories reviewed herein was supported by grants from the National Cancer Institute.
6,895 citations