Paclitaxel increases p21 synthesis and accumulation of its AKT-phosphorylated form in the cytoplasm of cancer cells

Heliez, Christophe; Baricault, Laurent; Barboule, Nadia; Valette, Annie

doi:10.1038/sj.onc.1206409

Cited by 56 publications

(53 citation statements)

References 29 publications

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“…29 Our results show that nuclear localization of cyclin B1 is strongly associated with sensitivity of OSCC cells to microtubule inhibitors, which is consistent with an earlier report showing that nuclear localization of cyclin B1 correlates with sensitivity of chemotherapeutic drugs and that leptomycin B, an inhibitor of nuclear export of cyclin B1, sensitizes cancer cells to chemotherapeutic drugs. 9 The mechanism by which nuclear localization of cyclin B1 triggers apoptotic signaling remains unknown, however.…”

Section: Discussionsupporting

confidence: 80%

Small interfering RNA-induced CHFR silencing sensitizes oral squamous cell cancer cells to microtubule inhibitors

Ogi

Toyota

Mitsuya³

et al. 2005

Cancer Biology & Therapy

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Alterations in the function of cell cycle checkpoints are frequently detected in oral squamous cell carcinomas (OSCCs), and are often associated with the sensitivity of the cancer cells to chemotherapeutic drugs. Recently, a mitotic checkpoint gene, Chfr, was shown to be inactivated by promoter methylation and point mutations in various human tumors. Here we show that the absence of its product, CHFR, is associated with mitotic checkpoint dysfunction, and that cancer cells lacking CHFR are sensitive to microtubule inhibitors. Checkpoint impairment appears to be caused by a prophase defect in this case, as OSCC cells lacking CHFR showed phosphorylation of histone H3 on Ser10 and translocation of cyclin B1 to the nucleus. When CHFR-deficient OSCC cells were treated with a microtubule inhibitor (docetaxel or paclitaxel), significant numbers of apoptotic cells were observed. Moreover, disruption of CHFR using small interfering RNA (siRNA) impaired the mitotic checkpoint, thereby reducing the ability of OSCC cells to arrest at G 2 /M phase and making them more sensitive to microtubule inhibitors. Our results suggest that CHFR could be a useful molecular target for chemotherapy.

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Section: Discussionsupporting

confidence: 80%

Small interfering RNA-induced CHFR silencing sensitizes oral squamous cell cancer cells to microtubule inhibitors

Ogi

Toyota

Mitsuya³

et al. 2005

Cancer Biology & Therapy

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“…Akt activated by Her-2/neu phosphorylates Thr-145 and Ser-146 within the nuclear localization signal of p21 (21,30,48). Phosphorylation of p21 by Akt has been shown to promote association with 14-3-3 proteins, which function as nuclear export proteins (49). In the current study, we have FIG.…”

Section: Discussionmentioning

confidence: 61%

Mirk/Dyrk1B Mediates Survival during the Differentiation of C2C12Myoblasts

Mercer

Ewton

Deng

et al. 2005

Journal of Biological Chemistry

110

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The kinase Mirk/dyrk1B is essential for the differentiation of C2C12 myoblasts. Mirk reinforces the G 0 /G 1 arrest state in which differentiation occurs by directly phosphorylating and stabilizing p27Kip1 and destabilizing cyclin D1. We now demonstrate that Mirk is antiapoptotic in myoblasts. Knockdown of endogenous Mirk by RNA interference activated caspase 3 and decreased myoblast survival by 75%, whereas transient overexpression of Mirk increased cell survival. Mirk exerts its anti-apoptotic effects during muscle differentiation at least in part through effects on the cell cycle inhibitor and pro-survival molecule p21Cip1 . Overexpression and RNA interference experiments demonstrated that Mirk phosphorylates p21 within its nuclear localization domain at Ser-153 causing a portion of the typically nuclear p21 to localize in the cytoplasm. Phosphomimetic GFP-p21-S153D was pancellular in both cycling C2C12 myoblasts and NIH3T3 cells. Endogenous Mirk in myotubes and overexpressed Mirk in NIH3T3 cells were able to cause the pancellular localization of wild-type GFPp21 but not the nonphosphorylatable mutant GFP-p21-S153A. Translocation to the cytoplasm enables p21 to block apoptosis through inhibitory interaction with pro-apoptotic molecules. Phosphomimetic p21-S153D was more effective than wild-type p21 in blocking the activation of caspase 3. Transient expression of p21-S153D also increased myoblast viability in colony forming assays, whereas the p21-S153A mutant had no effect. This Mirk-dependent change in p21 intracellular localization is a natural part of myoblast differentiation. Endogenous p21 localized exclusively to the nuclei of proliferating myoblasts but was also found in the cytoplasm of post-mitotic multinucleated myotubes and adult human skeletal myofibers.

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“…47,48 Hence, we postulate that HDAC2 can regulate both the expression and localization of p21 Cip1/WAF1 in the cell. As p53 is a known regulator of p21…”

Section: Discussionmentioning

confidence: 99%

Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1/WAF1 expression, independent of histone deacetylase 1

et al. 2005

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Histone deacetylases (HDACs) 1 and 2 share a high degree of homology and coexist within the same protein complexes. Despite their close association, each possesses unique functions. We show that the upregulation of HDAC2 in colorectal cancer occurred early at the polyp stage, was more robust and occurred more frequently than HDAC1. Similarly, while the expression of HDACs1 and 2 were increased in cervical dysplasia and invasive carcinoma, HDAC2 expression showed a clear demarcation of high-intensity staining at the transition region of dysplasia compared to HDAC1. Upon HDAC2 knockdown, cells displayed an increased number of cellular extensions reminiscent of cell differentiation. There was also an increase in apoptosis, associated with increased p21Cip1/WAF1 expression that was independent of p53. These results suggest that HDACs, especially HDAC2, are important enzymes involved in the early events of carcinogenesis, making them candidate markers for tumor progression and targets for cancer therapy.

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Paclitaxel increases p21 synthesis and accumulation of its AKT-phosphorylated form in the cytoplasm of cancer cells

Cited by 56 publications

References 29 publications

Small interfering RNA-induced CHFR silencing sensitizes oral squamous cell cancer cells to microtubule inhibitors

Small interfering RNA-induced CHFR silencing sensitizes oral squamous cell cancer cells to microtubule inhibitors

Mirk/Dyrk1B Mediates Survival during the Differentiation of C2C12Myoblasts

Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1/WAF1 expression, independent of histone deacetylase 1

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