Genomic instability due to germline p53 mutations drives preneoplastic progression toward cancer in human cells
TL;DR: Although p53 has been shown to be able to function as a transcription factor, mutations in p53 appear to affect genomic stability in LFS fibroblasts with double minutes and telomeric associations being prominent early events.
Abstract: Cells heterozygous for mutations in p53 demonstrate extreme genomic instability and develop mutations detectable at the chromosome level as well as the molecular level. This genomic instability causes initially nontumorigenic ras-expressing immortal LFS cells to progress to a tumorigenic state presumably due to additional mutational events. It is not surprising that LFS families with these p53 mutations develop the additional mutations necessary for cancer to occur at such high frequencies. This observation is consistent with increased cancer rates in these families being due to abrogation of a rate limiting step rather than a rate expected for one less step in a multistep carcinogenic process. Although p53 has been shown to be able to function as a transcription factor, mutations in p53 appear to affect genomic stability in LFS fibroblasts with double minutes and telomeric associations being prominent early events. One possibility is that p53 controls the expression of genes required for fidelity of replication or telomerase activity. Alternatively p53 may itself be a replication factor like the transcription factor CTF. In the future, we plan to investigate whether p53 plays a direct role in replication.
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TL;DR: The regulated expression of wild-type p53 resulted in the recovery of normal levels of repair of both cyclobutane pyrimidine dimers and 6-4 photoproducts in genomic DNA, but did not alter the transcription-coupled repair of cyclobUTane p SkyrimidineDimers.
371 citations
TL;DR: Tumors with TP53 mutations differ from their non-mutated counterparts in RNA, miRNA, and protein expression patterns, with mutant TP53 tumors displaying enhanced expression of cell cycle progression genes and proteins.
336 citations
TL;DR: As cancer chemotherapy relies primarily on the selective killing of cancer cells by DNA-damaging agents, genetic alterations affecting cellular stress response pathways may affect the outcome of cancer treatment.
Abstract: Mammalian cells are exposed to a wide variety of genotoxic stresses from both endogenous and exogenous sources. Cells typically exhibit cell cycle delays, or checkpoints, in response to acute genotoxic stress. Other types of cellular responses to DNA damage include apoptosis and probably increases in DNA repair levels. These response pathways are altered in cancer cells, by genetic alterations such as overexpression or mutation of oncogenes, or loss of tumor suppressor gene functions. As cancer chemotherapy relies primarily on the selective killing of cancer cells by DNA-damaging agents, genetic alterations affecting cellular stress response pathways may affect the outcome of cancer treatment.
128 citations
TL;DR: It is shown that Pin1 regulates the turnover of cyclin E in mouse embryo fibroblasts and predisposes Pin1 null mouse embryos to undergo more rapid genomic instability when immortalized by conditional inactivation of p53 and sensitizes these cells to more aggressive Ras-dependent transformation and tumorigenesis.
88 citations
TL;DR: The mechanisms of p53's control of the cell cycle, genomic stability, and apoptosis are reviewed and the way loss of these functions plays a role in tumor cell progression is reviewed.
Abstract: Publisher Summary The p53 tumor suppressor protein was first described in 1979 as a protein that binds SV40 virus large T antigen and independently as a tumor antigen. The chapter introduces p53 in tumor progression, and it focuses on the role of p53 in tumor progression. In particular, the mechanisms of p53's control of the cell cycle, genomic stability, and apoptosis are reviewed and the way loss of these functions plays a role in tumor cell progression. The chapter discusses the biochemical activities of p53. The chapter discusses p53 and cell cycle control and describes the control of G1/S by p53, control of G2/M by p53, and non transcriptional controls of cell cycle by p53. p53 and Apoptosis is discussed in the chapter, where p53 control of apoptosis in tumors, p53 transactivation and apoptosis, and non transactivator function in apoptosis by p53 are described in detail. The chapter describes p53 and tumor progression, apoptosis and tumor progression, growth control and tumor progression, and genomic instability and tumor progression.
81 citations
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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
"Genomic instability due to germline..." refers background in this paper
...Heterozygous germline p53 mutations were found in five out of five of families [12]....
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TL;DR: Loss of wild-type p53 may lead to amplification, possibly caused by changes in cell cycle progression, since tumor cells with wild- type p53 have the ability to amplify genes.
1,332 citations
Journal Article•
TL;DR: The diversity of tumor types in this syndrome suggests pathogenetic mechanisms which differ from hereditary cancers arising in single organs or tissues and laboratory markers are needed to identify high-risk individuals and families and to provide insights into susceptibility mechanisms that may be shared by a wide variety of cancers.
Abstract: A search of the Cancer Family Registry of the National Cancer Institute revealed 24 kindreds with the syndrome of sarcoma, breast carcinoma, and other neoplasms in young patients. Cancer developed in an autosomal dominant pattern in 151 blood relatives, 119 (79%) of whom were affected before 45 years of age. These young patients had a total of 50 bone and soft tissue sarcomas of diverse histological subtypes and 28 breast cancers. Additional features of the syndrome included an excess of brain tumors (14 cases), leukemia (9 cases), and adrenocortical carcinoma (4 cases) before age 45 years. These neoplasms also accounted for 73% of the multiple primary cancers occurring in 15 family members. Six of these patients had second cancers linked to radiotherapy. The diversity of tumor types in this syndrome suggests pathogenetic mechanisms which differ from hereditary cancers arising in single organs or tissues. The syndrome is presently diagnosed on clinical grounds; laboratory markers are needed to identify high-risk individuals and families and to provide insights into susceptibility mechanisms that may be shared by a wide variety of cancers.
1,242 citations
"Genomic instability due to germline..." refers background in this paper
...Li and Fraumeni have described a familial cancer syndrome that is characterized by multiple primary tumors, an early age of onset, and marked variation in tumor type [1, 2]....
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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
"Genomic instability due to germline..." refers background in this paper
...Southern blot analysis of Rsa I digested genomic DNA hybridized to the polymorphic VNTR probe, pYNZ22, has shown loss of heterozygosity in a region close to p53 for patient fibroblasts MDAH041 and MDAH087 during crisis at 26 and 37 pd, respectively [13]....
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...It appears from cell cycle analysis that the p53 regulates a checkpoint in G1 for the nucleotide synthesis inhibitor PALA, N-(phosphonoacetyl)-L-aspartate, which can be restored in immortal LFS fibroblasts transfected with a wild type p53 [13]....
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TL;DR: While suggesting the role of inheritance, the familial patterns seen with rhabdomyosarcoma may result from an interaction of genetic and environmental (?viral) fadors.
Abstract: To study the origins of childhood rhabdomyosarcoma, an examination was made of the 418 death certificates of U.S. children who died of this neoplasm, 1960-64, and of 280 medical charts from 17 hospital centers. Of exceptional interest was the presence in 5 Families of a second child with a soft-tissue sarcoma, 3 sibs (vs. 0.06 expeded by chance), and 2 cousins. The parents, grandparents, and other relatives of children in these families had a high Frequency of carcinoma ofthe breastand diverse neoplasms (e.g., acute leukemia and carcinomas of the lung, pancreas, and skin) at relatively young ages, suggesting a new Familial syndrome of multiple primary cancers. Additional components of the syndrome were implicated by the occurrence of adrenocortical carcinoma and brain tumor in the ~rst degree relatives of 2 other children with rhabdomyosarcoma. While suggesting the role of inheritance, the familial patterns seen with rhabdomyosarcoma may result from an interaction of genetic and environmental (?viral) fadors. The oncogenic agents and mechanisms in human cancer may be identified by the use of such family aggregations For laboratory studies and Further epidemiologic studies. Like most childhood neoplasms, rhabdomyosarcoma showed a peak mortality beFore 4 years of age and occurred slightly more often in males. This neoplasm was diagnosed in 29 children in the hospital series beFore 1 year of age and in 9 within 1 month of birth; this indicates that rhabdomyosarcoma may arise in utero. Unlike most neoplasms of
435 citations
"Genomic instability due to germline..." refers background in this paper
...Li and Fraumeni have described a familial cancer syndrome that is characterized by multiple primary tumors, an early age of onset, and marked variation in tumor type [1, 2]....
[...]