Mutant p53 and genomic instability in a transgenic mouse model of breast cancer

Murphy, Kristen L; Rosen, Jeffrey M.

doi:10.1038/sj.onc.1203274

Cited by 34 publications

(24 citation statements)

References 46 publications

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“…The impact of p53-dependent transcriptional regulation on centromeric factors is thus important to consider. Indeed, p53 is known to sense chromosomal breaks and defects induced by mitotic dysfunction and respond by promoting cell cycle arrest to prevent genome instability (Harvey et al 1993;Murphy and Rosen 2000;Ghiselli 2006;Kim et al 2009;Lambrus et al 2015;Ohashi et al 2015) Such defects comprise aneuploidy (defined as hyperploid and hypoploid chromosome numbers), which is a frequent outcome of aberrant mitosis and gives rise to genome instability, a hallmark of cancer (Santaguida and Amon 2015). In cells with functional p53, defects in chromosome segregation activate p53 by several mechanisms, mediated in part by ATM or p38 (Santaguida and Amon 2015).…”

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confidence: 99%

Essential role for centromeric factors following p53 loss and oncogenic transformation

et al. 2017

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In mammals, centromere definition involves the histone variant CENP-A (centromere protein A), deposited by its chaperone, HJURP (Holliday junction recognition protein). Alterations in this process impair chromosome segregation and genome stability, which are also compromised by p53 inactivation in cancer. Here we found that CENP-A and HJURP are transcriptionally up-regulated in p53-null human tumors. Using an established mouse embryonic fibroblast (MEF) model combining p53 inactivation with E1A or HRas-V12 oncogene expression, we reproduced a similar up-regulation of HJURP and CENP-A. We delineate functional CDE/CHR motifs within the Hjurp and Cenpa promoters and demonstrate their roles in p53-mediated repression. To assess the importance of HJURP up-regulation in transformed murine and human cells, we used a CRISPR/Cas9 approach. Remarkably, depletion of HJURP leads to distinct outcomes depending on their p53 status. Functional p53 elicits a cell cycle arrest response, whereas, in p53-null transformed cells, the absence of arrest enables the loss of HJURP to induce severe aneuploidy and, ultimately, apoptotic cell death. We thus tested the impact of HJURP depletion in pre-established allograft tumors in mice and revealed a major block of tumor progression in vivo. We discuss a model in which an "epigenetic addiction" to the HJURP chaperone represents an Achilles' heel in p53-deficient transformed cells.

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confidence: 99%

Essential role for centromeric factors following p53 loss and oncogenic transformation

et al. 2017

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“…As aneuploidy is characteristic of mammary tumors arising in the WAPp53 172R-H mice (12,18,20,21), studies were undertaken to examine the effect of expression of this mutant p53 on centrosome number in vitro. p53-null mouse MECs were transiently transfected with constructs encoding either wild-type p53 or the p53 172R-H mutant.…”

Section: Transient Expression Of the P53 172r-h Mutant Results In Incmentioning

confidence: 99%

“…Increased chromosome number, but no change in sister chromatid exchange in cells stably expressing p53 172R-H Mammary tumors arising in mice carrying the p53 172R-H transgene are frequently aneuploid (12,18,20,21). To assess the effect of this p53 mutant on ploidy in vitro, metaphase spreads (Fig.…”

Section: Lower Basal Levels Of Apoptosis and Increased Resistance To mentioning

confidence: 99%

Functional Significance of Mutant p53 in Breast Cancer

O'Lear¹,

Rosen²

2000

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Washington Headquarters Services, Directorate for Information Operations and Reports. 1215 Jefferson Davis Highway, Suite 1204, Arlington VA 22202-4302, and to the Office of Management and Budget. Paperwork Reduction Project (0704-0188), Washington, DC 20503 AGENCY USE ONLY (Leave blank) REPORT DATE July 2000 REPORT TYPE AND DATES COVERED- Annual Summary(1 Jul 99-30 Jun 00) TITLE AND SUBTITLE Functional Significance of Mutant p53 in Breast Cancer AUTHOR(S)Kristen Murphy, Ph.D. Renee 0'Lear Jeffrey Rosen, Ph.D. FUNDING NUMBERS.DAMD17-99-1-9074 PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)Baylor College of Medicine Houston, TX 77030-3498 E-Mail: rr044669@bcm.tmc.edu Approximately 40% of breast cancer patients have tumors containing alterations in the p53 tumor suppressor gene; these patients are known to have a poorer prognosis than those lacking p53 mutations. Arg-His (R-H) mutations are frequently observed at amino acid 175 of p53 (equivalent to murine 172) in such tumors. PERFORMING ORGANIZATION REPORT NUMBER SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES)UExpression of a mammary-targeted p53 172R-H transgene rarely induces spontaneous tumors in mice, but carcinogen-treated p53 172R-H transgenic mice develop tumors much earlier than controls.Furthermore, expression of this transgene predisposes tumors induced by carcinogen treatment or oncogene coexpression to the development of aneuploidy.The objective of this proposal is to examine the mechanism by which this particular p53 mutant promotes aneuploidy and tumorigenesis.This will be accomplished through both analysis of gene transcription and analysis of the mitotic machinery and cellular apoptosis.Recent in vitro studies indicate that expression of the p53 175R-H mutant in mammary epithelial cells may promote mammary tumorigenesis by deregulating centrosome replication and reducing both basal and DNA-damage-induced apoptosis.Transcriptional regulation studies are currently in progress to identify possible novel protein-protein interactions between the mutant and other proteins leading to the up-or down-regulation of genes linked to the promotion of SUBJECT TERMS IntroductionApproximately 50% of human cancers have p53 alterations, and patients with these cancers have poorer prognoses. When functional, the p53 protein blocks proliferation of cells that have sustained DNA damage and induces apoptosis in cells too badly damaged to undergo repair. Mutant forms of p53 are often no longer protective, and in many cases have acquired additional functions which make them more deleterious than the simple absence of wild-type p53. ...

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“…A 'superactive' mutant p53 transgene, p53-R172L, expressed under the WAP promoter results in elevated apoptosis rates in normal mammary glands [49,50]. Interestingly, this transgene delayed mammary tumor onset induced by DMBA [50] and in transgenic mice expressing transforming growth factor a [26]. In these models, protection against breast cancer by p53 may thus be due to removal of genetically damaged cells by p53-dependent apoptosis.…”

Section: Loss Of P53 Function Is Critical In Brcat-associated and Brcmentioning

confidence: 99%

Development of Spontaneous Mammary Tumors in BALB/c-p53+-Mice: Detection of Early Genetic Alterations and the Mapping of BALB/c Susceptibility Genes

Hill¹,

Jerry²

2002

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Mutant p53 and genomic instability in a transgenic mouse model of breast cancer

Cited by 34 publications

References 46 publications

Essential role for centromeric factors following p53 loss and oncogenic transformation

Essential role for centromeric factors following p53 loss and oncogenic transformation

Functional Significance of Mutant p53 in Breast Cancer

Development of Spontaneous Mammary Tumors in BALB/c-p53+-Mice: Detection of Early Genetic Alterations and the Mapping of BALB/c Susceptibility Genes

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