Abnormal Centrosome Amplification in the Absence of p53

Fukasawa, Kenji; Choi, Tae-Saeng; Kuriyama, Ryoko; Rulong, Shen; Woude, George F. Vande

doi:10.1126/science.271.5256.1744

Cited by 747 publications

(600 citation statements)

References 42 publications

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“…Finally, as mentioned previously, p53 has been implicated in regulation of the G2/M checkpoint and mitosis, with particularly striking e ects upon centrosomal duplication (Fukasawa et al, 1996). Carcinogeninduced primary skin tumors from mice bearing a skintargeted 172 R ± H mutation displayed a much greater degree of aberrant centrosomal duplication than did tumors from p53-null mice, also supporting a gain-offunction e ect of this mutation (Wang XJ and Roop DR, personal communication).…”

Section: Discussionmentioning

confidence: 54%

A transgenic mouse model for mammary carcinogenesis

Murphy

Laucirica³

et al. 1998

Oncogene

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Missense mutations in the p53 tumor suppressor occur frequently in human breast cancer and in¯uence both the prognosis and response to chemotherapy. Amino acid 175 (equivalent to murine 172) is the second most common site of missense mutations in p53 in human breast cancer. Over 95% of these mutations are arginine-to-histidine (R-H) substitutions resulting in a gain-of-function, and not merely a dominant-negative phenotype. Transgenic mice expressing a p53 172 R ± H construct targeted to the mammary gland by means of a whey acidic protein (WAP) promoter were characterized as a model system in order to determine the speci®c e ects of this mutation on mammary tumorigenesis. Although transgene expression alone had no apparent e ect on normal mammary development, transgenic mice treated with the chemical carcinogen dimethylbenz(a)anthracene developed tumors with much shorter latency than did control littermates and had a greater tumor burden. Tumors arising in transgenic mice did not exhibit either decreased apoptosis or increased cell proliferation relative to tumors arising in nontransgenic littermates, but did display increased genomic instability. Large pleiomorphic nuclei were visible in many tumors from transgenic mice, and DNĀ ow analysis con®rmed the presence of signi®cant aneuploid cell populations. Since these transgenic mice develop very few spontaneous tumors, while accelerating carcinogen-and oncogene-mediated tumorigenesis, this mouse model will, therefore, be useful in the investigation of early events in mammary tumorigenesis. It may also be used as a preclinical model to test newly developed chemotherapeutic strategies.

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Section: Discussionmentioning

confidence: 54%

A transgenic mouse model for mammary carcinogenesis

Murphy

Laucirica³

et al. 1998

Oncogene

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“…Functional deregulation and centrosome amplification which leads to abnormal spindle formation and chromosomal instability is strongly associated with tumorigenesis (Fukasawa et al, 1996;D'Assoro et al, 2002). Studies have shown that BRCA1 localizes to the centrosome and binds to g-tubulin, a major component of centrosomes (Starita et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

MTA1-mediated transcriptional repression of BRCA1 tumor suppressor gene

et al. 2007

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Metastasis-associated tumor antigen 1 (MTA1), a component of the nucleosome remodeling and deacetylating (NuRD) complex is routinely upregulated in several cancers. In the present study, we investigated the potential role of MTA1 in BRCA1 transcriptional repression and subsequent chromosomal instability. MTA1-NuRD complex was found to negatively regulate BRCA1 transcription by physically associating with an atypical estrogen-responsive element (ERE) on the BRCA1 promoter. Moreover, MTA1 and HDAC complex recruited to the ERE of BRCA1 promoter in an ER a-dependent manner. Accordingly, BRCA1 protein levels were enhanced by silencing of either MTA1 expression or by treatment with the specific histone deacetylase inhibitor trichostatin A. MTA1's strong repressive effects on BRCA1 expression was supported by our observation that cells stably overexpressing MTA1 showed centrosome amplification which has been long implicated as a phenotype for BRCA1 repression. Accordingly, overexpression of BRCA1 in cells stably over expressing MTA1 resulted in restoration of normal centrosome numbers. Together, these findings strongly implicate MTA1 in the transcriptional repression of BRCA1 leading to abnormal centrosome number and chromosomal instability.

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“…23,24 The more general tumor suppressor gene p53 has also been shown to localize to centrosomes and regulate centrosome duplication in a manner independent of its function as a transcription factor. 25 Another important group of proteins associated with the centrosomes are kinases like Aurora and Polo-like kinases (Plk) that are important for the integrity and correct separation of the mitotic spindle and therefore also for accurate segregation of chromosomes and correct cytokinesis (reviewed in references 26 -29). Overexpression of these kinases can be observed in tumors and correlated with centrosome amplification and aneuploidy.…”

Section: Discussionmentioning

confidence: 99%

PIBF (progesterone induced blocking factor) is overexpressed in highly proliferating cells and associated with the centrosome

Lachmann

Gelbmann

Kálmán

et al. 2004

Intl Journal of Cancer

103

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PIBF was previously identified as a 34 kDa immunomodulatory molecule secreted by pregnancy lymphocytes and is thought to play a crucial role in preventing rejection of the embryo by the maternal immune response. Recent data suggested that PIBF protein was also expressed by the progesterone receptor (PR) positive MCF-7 breast tumor cell line. Given the notion that a number of proteins shown to be involved in tumorigenesis are associated with the centrosome and disturbed centrosome function causes unequal segregation of chromosomes, studies to evaluate whether or not PIBF that is highly expressed in tumors is directly involved in tumorigenesis are thus warranted.

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Abnormal Centrosome Amplification in the Absence of p53

Cited by 747 publications

References 42 publications

A transgenic mouse model for mammary carcinogenesis

A transgenic mouse model for mammary carcinogenesis

MTA1-mediated transcriptional repression of BRCA1 tumor suppressor gene

PIBF (progesterone induced blocking factor) is overexpressed in highly proliferating cells and associated with the centrosome

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