Genotoxic stress leads to centrosome amplification in breast cancer cell lines that have an inactive G1/S cell cycle checkpoint

D’Assoro, Antonino B.; Busby, Robert C.; Suino, Kelly M; Delva, Emmanuella; Almodóvar-Mercado, Gustavo J.; Johnson, Holly L.; Folk, Christopher; Farrugia, Daniel J.; Vasile, Vlad C.; Stivala, Franca; Salisbury, Jeffrey L.

doi:10.1038/sj.onc.1207568

Cited by 69 publications

(80 citation statements)

References 46 publications

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“…As HU-treated cells are cell cycle arrested in S phase and the a-amanitin concentrations used did not cause a cell cycle arrest (Figure 1c), this decrease of numerical centriole abnormalities is unrelated to nonspecific cell cycle effects of a-amanitin. The finding that not all cells treated with HU showed overduplication of centrioles is in line with previous reports (Balczon et al, 1995) and most likely based on the fact that a relaxation of an intrinsic block to reduplication (Wong and Stearns, 2003) occurs only in a proportion of cells (Matsumoto et al, 1999;Meraldi et al, 1999;D'Assoro et al, 2004).…”

Section: A-amanitin Inhibits Hpv-16 E7-and Hu-induced Centriole Overdsupporting

confidence: 91%

RNA polymerase II transcription is required for human papillomavirus type 16 E7- and hydroxyurea-induced centriole overduplication

et al. 2006

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Aberrant centrosome numbers are detected in virtually all human cancers where they can contribute to chromosomal instability by promoting mitotic spindle abnormalities. Despite their widespread occurrence, the molecular mechanisms that underlie centrosome amplification are only beginning to emerge. Here, we present evidence for a novel regulatory circuit involved in centrosome overduplication that centers on RNA polymerase II (pol II). We found that human papillomavirus type 16 E7 (HPV-16 E7)-and hydroxyurea (HU)-induced centriole overduplication are abrogated by a-amanitin, a potent and specific RNA pol II inhibitor. In contrast, normal centriole duplication proceeded undisturbed in a-amanitin-treated cells. Centriole overduplication was significantly reduced by siRNA-mediated knock down of CREB-binding protein (CBP), a transcriptional co-activator. We identified cyclin A2 as a key transcriptional target of RNA pol II during HU-induced centriole overduplication. Collectively, our results show that ongoing RNA pol II transcription is required for centriole overduplication whereas it may be dispensable for normal centriole duplication. Given that many chemotherapeutic agents function through inhibition of transcription, our results may help to develop strategies to target centrosomemediated chromosomal instability for cancer therapy and prevention.

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Section: A-amanitin Inhibits Hpv-16 E7-and Hu-induced Centriole Overdsupporting

confidence: 91%

RNA polymerase II transcription is required for human papillomavirus type 16 E7- and hydroxyurea-induced centriole overduplication

et al. 2006

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“…One mechanism for preservation of genomic stability is through p53-mediated control of centrosome homeostasis (Fukasawa, 2005). Several studies have demonstrated that following DNA damage, centrosome homeostasis is maintained through the G 1 /S cell cycle checkpoint by p53 transcriptional activation of the cdk inhibitor p21 (Bennett et al, 2004;D'Assoro et al, 2004). However, whether abrogation of p53 function contributes to cancer cell heterogeneity through development of centrosome amplification during breast cancer progression has not been established.…”

Section: Discussionmentioning

confidence: 99%

“…The human breast cancer cell line, MCF-7 (ATCC, Manassas, VA, USA), was modified to express a recombinant GFPcentrin2 chimera (MCF-7 GFPÀcetn2 ) and a temperature sensitive p53 construct mutated at residue 135 of valine (vMCF-7 DNp53 ) as described previously (Knippschild et al, 1996;D'Assoro et al, 2001D'Assoro et al, , 2004. For imaging of tumor localization and growth in living animals, cells were engineered to express a firefly luciferase protein (Hasegawa et al, 2006).…”

Section: Human Breast Cancer Cell Linesmentioning

confidence: 99%

“…Centrosome homeostasis is disrupted in cancer cells lacking normal function of the tumor suppressors p53 and Rb or deregulated activity of cdk2 and/or mitotic kinases, leading to centriole reduplication (Fukasawa et al, 1996;D'Assoro et al, 2004;Hernando et al, 2004;Duensing et al, 2006aDuensing et al, , b, 2007Fukasawa, 2007). Furthermore, following treatment with anticancer genotoxic agents, centrosome amplification and consequent chromosomal instability are exacerbated in cancer cells lacking p53 function (Bennett et al, 2004;D'Assoro et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, following treatment with anticancer genotoxic agents, centrosome amplification and consequent chromosomal instability are exacerbated in cancer cells lacking p53 function (Bennett et al, 2004;D'Assoro et al, 2004). Importantly, human breast tumors with abrogated p53 function are also frequently ERa negative and display more aggressive behavior (Angeloni et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Impaired p53 function leads to centrosome amplification, acquired ERα phenotypic heterogeneity and distant metastases in breast cancer MCF-7 xenografts

et al. 2008

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MASTL: A novel therapeutic target for Cancer Malignancy

2020

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Targeting mitotic kinases is an emerging anticancer approach with promising preclinical outcomes. Microtubule‐associated serine/threonine kinase like (MASTL), also known as Greatwall (Gwl), is an important mitotic kinase that regulates mitotic progression of normal or transformed cells by blocking the activity of tumor suppressor protein phosphatase 2A (PP2A). MASTL upregulation has now been detected in multiple cancer types and associated with aggressive clinicopathological features. Apart, an aberrant MASTL activity has been implicated in oncogenic transformation through the development of chromosomal instability and alteration of key oncogenic signaling pathways. In this regard, recent publications have revealed potential role of MASTL in the regulation of AKT/mTOR and Wnt/β‐catenin signaling pathways, which may be independent of its regulation of PP2A‐B55 (PP2A holoenzyme containing a B55‐family regulatory subunit). Taken together, MASTL kinase has emerged as a novel target for cancer therapeutics, and hence development of small molecule inhibitors of MASTL may significantly improve the clinical outcomes of cancer patients. In this article, we review the role of MASTL in cancer progression and the current gaps in this knowledge. We also discuss potential efficacy of MASTL expression for cancer diagnosis and therapy.

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Genotoxic stress leads to centrosome amplification in breast cancer cell lines that have an inactive G1/S cell cycle checkpoint

Cited by 69 publications

References 46 publications

RNA polymerase II transcription is required for human papillomavirus type 16 E7- and hydroxyurea-induced centriole overduplication

RNA polymerase II transcription is required for human papillomavirus type 16 E7- and hydroxyurea-induced centriole overduplication

Impaired p53 function leads to centrosome amplification, acquired ERα phenotypic heterogeneity and distant metastases in breast cancer MCF-7 xenografts

MASTL: A novel therapeutic target for Cancer Malignancy

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