BRCA1 Interacts with and Is Required for Paclitaxel-Induced Activation of Mitogen-Activated Protein Kinase Kinase Kinase 3

Gilmore, Paula M.; McCabe, Nuala; Quinn, Jennifer E.; Kennedy, Richard D.; Gorski, Julia J.; Andrews, Heather N.; McWilliams, Stewart; Carty, Michael; Mullan, Paul B.; Duprex, W. Paul; Liu, Edison T.; Johnston, Patrick G.; Harkin, D. Paul

doi:10.1158/0008-5472.can-03-4080

Cited by 43 publications

(30 citation statements)

References 38 publications

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“…It is not known at present how BRCA1 enhances spindle arrest in response to these drugs but this may be due in part to its association with and subsequent activation of MEKK3 following microtubule damage (Gilmore et al, 2004). We previously demonstrated that inducible expression of GADD45 also activated the G2/M checkpoint in response to microtubule agents, suggesting that BRCA1-mediated transactivation of GADD45 may be important in the regulation of the mitotic checkpoint (Mullan et al, 2001).…”

Section: Mitotic Checkpointmentioning

confidence: 99%

The role of BRCA1 in transcriptional regulation and cell cycle control

2006

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The exact functions of BRCA1 have not been fully described but it now seems apparent that it has roles in DNA damage repair, transcriptional regulation, cell cycle control and most recently in ubiquitylation. These functions of BRCA1 are most likely interdependent but this review will focus on the role of BRCA1 in relation to transcriptional regulation and in particular how this impacts upon cell cycle control. We will (i) describe the structure of BRCA1 and how it may contribute to its transcription function; (ii) describe the interaction of BRCA1 with the core transcriptional machinery (RNA polII); (iii) describe how BRCA1 may regulate transcription at an epigenetic level through chromatin modification; (iv) discuss the role of BRCA1 in modulating transcription through its association with sequence-specific transcription factors. Finally, we will discuss the possible effects of BRCA1 transcriptional regulation on downstream targets with known roles in cell cycle control.

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Section: Mitotic Checkpointmentioning

confidence: 99%

The role of BRCA1 in transcriptional regulation and cell cycle control

2006

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“…The gene is involved in a variety of cellular processes, including apoptosis [23,24] . Quinn et al [24] found that the presence of BRCA1 causes breast cancer cells to undergo enhanced levels of apoptosis by mitotic-spindle-poisoning agents such as paclitaxel.…”

Section: Synergistic Interaction Between Paclitaxel and Zoledronic Acmentioning

confidence: 99%

Mechanisms of the Synergistic Interaction between the Bisphosphonate Zoledronic Acid and the Chemotherapy Agent Paclitaxel in Breast Cancer Cells in vitro

et al. 2006

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Breast cancer patients often receive both paclitaxel and zoledronic acid as part of their treatment, and these drugs are reported to have synergistic effects on the induction of apoptosis of breast cancer cells in vitro. We have found that the synergistic interaction is drug sequence dependent, with maximal levels of apoptosis achieved when cells are treated with paclitaxel followed by zoledronic acid, as opposed to the reverse sequence or simultaneous treatment. The synergistic interaction persists at clinically relevant concentrations and incubation periods. We report that the sequential treatment is associated with cell cycle changes and depends on breast cancer cell characteristics, with hormone independence, mutated p53 status and presence of BRCA1 gene being associated with higher levels of apoptosis. Finally, we have found that the synergistic induction of apoptosis is via zoledronic acid-mediated inhibition of the mevalonate pathway.

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“…Proinflammatory cytokines, including IFN-g, IL-1, and tumor necrosis factor-a, have been shown to activate MEKK1 or MEKK3 (40)(41)(42). In addition, MEKK3 activation has been linked to paclitaxel-induced, BRCA1-dependent apoptosis in breast cancer (43) and to TRAF7-mediated apoptosis (44) and MEKK3 has been shown to physically interact with BRCA1 and TRAF7. Although we have not been able to successfully measure MEKK kinase activity in our system, we did find that MEKK1, MEKK2, and MEKK3 were expressed in all three cell lines, and the degree of expression was not altered by either IFN-g or IFN-a.…”

Section: Effects Of Ifn-mentioning

confidence: 99%

Gene Expression Changes and Signaling Events Associated with the Direct Antimelanoma Effect of IFN-γ

et al. 2005

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IFN-; plays a role in the response to melanoma indirectly through its effect on the immune system and directly through its antiproliferative and proapoptotic effects on melanoma cells. To understand the molecular basis for the direct antimelanoma effect of IFN-;, we studied IFN-induced changes in gene expression and signaling among three human melanoma cell lines (DM6, DM93, and 501mel). These were resistant to the antimelanoma effect of IFN-A, and only DM6 cells exhibited growth inhibition and apoptosis with IFN-;. Through DNA microarray analysis, we found that the antimelanoma effect of IFN-; in DM6 was associated with the down-regulation of multiple genes involved in G-protein signaling and phospholipase C activation (including Rap2B and calpain 3) as well as the down-regulation of genes involved in melanocyte/melanoma survival (MITF and SLUG), apoptosis inhibition (Bcl2A1 and galectin-3), and cell cycling (CDK2). The antimelanoma effect of IFN-; was also associated with the up-regulation of the proapoptotic dependence receptor UNC5H2 and the Wnt inhibitor Dkk-1. Whereas both IFNs were able to activate Stat1 in all cell lines, the delayed activation of the extracellular signal-regulated kinase, p38, and c-Jun NH 2 -terminal kinase mitogen-activated protein kinases occurred only in DM6 with IFN-;, and the effect of IFN-; on cell growth and survival as well as gene expression in DM6 was dependent on the coordinate activation of MEK1 and p38. These findings provide new insights into the signaling events and gene expression changes associated with growth inhibition and apoptosis in melanoma and may thereby assist in identifying new targets for the treatment of melanoma.

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BRCA1 Interacts with and Is Required for Paclitaxel-Induced Activation of Mitogen-Activated Protein Kinase Kinase Kinase 3

Cited by 43 publications

References 38 publications

The role of BRCA1 in transcriptional regulation and cell cycle control

The role of BRCA1 in transcriptional regulation and cell cycle control

Mechanisms of the Synergistic Interaction between the Bisphosphonate Zoledronic Acid and the Chemotherapy Agent Paclitaxel in Breast Cancer Cells in vitro

Gene Expression Changes and Signaling Events Associated with the Direct Antimelanoma Effect of IFN-γ

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