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Author

Michael Mowat

Bio: Michael Mowat is an academic researcher from University of Toronto. The author has contributed to research in topics: Gene & Gene expression. The author has an hindex of 4, co-authored 5 publications receiving 640 citations. Previous affiliations of Michael Mowat include Ontario Institute for Cancer Research.
Topics: Gene, Gene expression, Friend virus, AKT1S1, Oncovirus

Papers
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Journal ArticleDOI
18 Apr 1985-Nature
TL;DR: It is demonstrated that genomic rearrangements are responsible for p53 gene Jnactivation in these cell lines and that they occur in vivo during the natural progression of Friend virus-induced erythroleukaemia.
Abstract: There is now good evidence that the cellular protein, p53, is involved in the transformation process, although its precise role is unknown1. It was reported recently that expression of the p53 gene can immortalize cells2 and that the p53 gene can replace the myc oncogene in a myc–ras immortalization/transformation assay3,4. We have investigated whether p53 is involved in the progression towards the neoplastic state in vivo and report here that erythroleukaemic cell lines transformed by different isolates of Friend leukaemia virus show altered expression of the cellular p53 gene. High levels of p53 protein are found in certain lines, but the protein is undetectable in others. This heterogeneity in p53 gene expression is associated with heterogeneity in tumorigenicity. We demonstrate that genomic rearrangements are responsible for p53 gene Jnactivation in these cell lines and that they occur in vivo during the natural progression of Friend virus-induced erythroleukaemia.

352 citations

Journal ArticleDOI
TL;DR: The inability of p53-negative tumor cell lines to support long-term expression of wild-type p53 protein is consistent with the view that p53 is a tumor suppressor gene.
Abstract: Inactivation of the cellular p53 gene is a common feature of Friend virus-induced murine erythroleukemia cell lines and may represent a necessary step in the progression of this disease. As well, frequent loss or mutation of p53 alleles in diverse human tumors is consistent with the view of p53 as a tumor suppressor gene. To examine the significance of p53 gene inactivation in tumorigenesis, we have attempted to express transfected wild-type p53 in three p53-negative tumor cell lines: murine DP16-1 Friend erythroleukemia cells, human K562 cells, and SKOV-3 cells. We found that aberrant p53 proteins, which differ from wild-type p53 by a single amino acid substitution, were expressed stably in these cells, whereas wild-type p53 expression was not tolerated. The inability of p53-negative tumor cell lines to support long-term expression of wild-type p53 protein is consistent with the view that p53 is a tumor suppressor gene.

125 citations

Journal ArticleDOI
TL;DR: This study represents the first description of an altered p53 gene product arising by mutation during neoplastic progression and identifies a region in the p53 protein molecule that plays a role in determining p53 stability in vivo.
Abstract: The p53 gene is rearranged in an erythroleukemic cell line (DP15-2) transformed by Friend retrovirus. Here, we characterize the mutation and identify a deletion of approximately equal to 3.0 kilobases that removes exon 2 coding sequences. The gene is expressed in DP15-2 cells and results in synthesis of a 44,000-dalton protein that is missing the N-terminal amino acid residues of p53. The truncated protein is unusually stable and accumulates to high levels intracellularly. Moreover, it appears to have undergone a change in conformation as revealed by epitope mapping studies. This study represents the first description of an altered p53 gene product arising by mutation during neoplastic progression and identifies a region in the p53 protein molecule that plays a role in determining p53 stability in vivo.

100 citations

Journal ArticleDOI
TL;DR: The results suggest that Friend tumor cells with rearrangements in their p53 gene arise as the result of a unique transformation event, rather than by progression from already existing tumor cellsWith a normal p53 genes, and suggest that such rearranges confer a strong selective advantage to these cells in vivo.
Abstract: The erythroleukemia induced by Friend virus complex in adult mice is a multistage malignancy characterized by the emergence, late in the disease, of tumorigenic cell clones. We have previously shown that a significant proportion of these clones have unique rearrangements in their cellular p53 oncogene. The clonal relationships among Friend tumor cells isolated in the late stages of Friend erythroleukemia were analyzed by examining the unique integration site of Friend murine leukemia virus and the unique rearrangement in their cellular p53 oncogene. The majority of clones isolated from individual mice infected with Friend virus were clonally related as judged by the site of Friend murine leukemia virus integration. However, Southern gel analysis of DNA from individual Friend cell clones indicated that all of the clones with a normal p53 gene from the same mice were clonally related, but were unrelated to the Friend cell lines with a rearranged p53 gene. These results suggest that Friend tumor cells with rearrangements in their p53 gene arise as the result of a unique transformation event, rather than by progression from already existing tumor cells with a normal p53 gene. They also suggest that such rearrangements in the p53 gene confer a strong selective advantage to these cells in vivo.

68 citations


Cited by
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Journal ArticleDOI
21 Dec 1990-Cell
TL;DR: It is demonstrated that the E6 proteins of the oncogenic HPVs that bind p53 stimulate the degradation of p53, which results in selective degradation of cellular proteins such as p53 with negative regulatory functions provides a novel mechanism of action for dominant-acting oncoproteins.

3,903 citations

Journal ArticleDOI
06 Jun 1991-Nature
TL;DR: The cell cycle is composed of a series of steps which can be negatively or postively regulated by various factors, chief among the negative regulators is the p53 protein, which can lead to cancer.
Abstract: The cell cycle is composed of a series of steps which can be negatively or positively regulated by various factors. Chief among the negative regulators is the p53 protein. Alteration or inactivation of p53 by mutation, or by its interactions with oncogene products of DNA tumour viruses, can lead to cancer. These mutations seem to be the most common genetic change in human cancers.

3,665 citations

Journal ArticleDOI
26 Jun 1992-Cell
TL;DR: A product of the mdm-2 oncogene forms a tight complex with the p53 protein, and the mDM-2oncogene can inhibit p53-mediated transactivation.

3,136 citations

Journal ArticleDOI
06 Apr 1990-Science
TL;DR: This study shows that the E6 protein of HPV-16 is capable of binding to the cellular p53 protein, providing further evidence that the human papillomaviruses, the adenovirus type 5, and SV40 may effect similar cellular pathways in transformation.
Abstract: Human papillomavirus type 16 (HPV-16) is a DNA tumor virus that is associated with human anogenital cancers and encodes two transforming proteins, E6 and E7. The E7 protein has been shown to bind to the retinoblastoma tumor suppressor gene product, pRB. This study shows that the E6 protein of HPV-16 is capable of binding to the cellular p53 protein. The ability of the E6 proteins from different human papillomaviruses to form complexes with p53 was assayed and found to correlate with the in vivo clinical behavior and the in vitro transforming activity of these different papillomaviruses. The wild-type p53 protein has tumor suppressor properties and has also been found in association with large T antigen and the E1B 55-kilodalton protein in cells transformed by SV40 and by adenovirus type 5, respectively, providing further evidence that the human papillomaviruses, the adenoviruses, and SV40 may effect similar cellular pathways in transformation.

2,520 citations

Journal ArticleDOI
25 Aug 1995-Cell
TL;DR: The results establish the role of p21CIP1/WAF1 in the G1 checkpoint, but suggest that the anti-apoptotic and theAnti-oncogenic effects of p53 are more complex.

2,100 citations