Identification of the nuclear localization signal of p21<sup>cip1</sup> and consequences of its mutation on cell proliferation

Rodríguez–Vilarrupla, Aina; Dı́az, Carmen; Canela, Núria; Rahn, Hans-Peter; Bachs, Oriol; Agell, Neus

doi:10.1016/s0014-5793(02)03549-4

Cited by 58 publications

(60 citation statements)

References 25 publications

(38 reference statements)

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“…Infected VK2/E6E7 and ME-180 cells both showed a redistribution of p21 and p27 to the nucleus at 6 hours. The p21 and p27 proteins are cell cycle inhibitors, and their nuclear localization is associated with a slowing of the cell cycle (Rodríguez-Vilarrupla et al, 2002;Sherr and Roberts, 1995). Hence, these data indicate a possible deceleration of the cell cycle during infection.…”

Section: Neisseria Gonorrhoeae Induces and Redistributes P21 And P27mentioning

confidence: 78%

Neisseria gonorrhoeae infection causes DNA damage and affects the expression of p21, p27 and p53 in non-tumor epithelial cells

Vielfort

Söderholm

Weyler

et al. 2013

Journal of Cell Science

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SummaryThe constant shedding and renewal of epithelial cells maintain the protection of epithelial barriers. Interference with the processes of host cell-cycle regulation and barrier integrity permits the bacterial pathogen Neisseria gonorrhoeae to effectively colonize and invade epithelial cells. Here, we show that a gonococcal infection causes DNA damage in human non-tumor vaginal VK2/E6E7 cells with an increase of 700 DNA strand breaks per cell per hour as detected by an alkaline DNA unwinding assay. Infected cells exhibited elevated levels of DNA double-strand breaks, as indicated by a more than 50% increase in cells expressing DNA damage-response protein 53BP1-positive foci that co-localized with phosphorylated histone H2AX (cH2AX). Furthermore, infected cells abolished their expression of the tumor protein p53 and induced an increase in the expression of cyclin-dependent kinase inhibitors p21 and p27 to 2.6-fold and 4.2-fold of controls, respectively. As shown by live-cell microscopy, flow cytometry assays, and BrdU incorporation assays, gonococcal infection slowed the host cell-cycle progression mainly by impairing progression through the G2 phase. Our findings show new cellular players that are involved in the control of the human cell cycle during gonococcal infection and the potential of bacteria to cause cellular abnormalities.

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Section: Neisseria Gonorrhoeae Induces and Redistributes P21 And P27mentioning

confidence: 78%

Neisseria gonorrhoeae infection causes DNA damage and affects the expression of p21, p27 and p53 in non-tumor epithelial cells

Vielfort

Söderholm

Weyler

et al. 2013

Journal of Cell Science

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“…Cancer Res 2007; 67: (24 knockdown of both p38a and p38h abrogated the checkpoint response to hydroxyurea only when Chk1 was inhibited by UCN01 at the same time. Consistent with this idea, knocking down Chk1 by transfecting specific siRNA allowed hydroxyurea-treated cells to enter mitosis only in the presence of the p38a/h inhibitor SB202190.…”

Section: Cancer Researchmentioning

confidence: 99%

Different S/M Checkpoint Responses of Tumor and Non–Tumor Cell Lines to DNA Replication Inhibition

et al. 2007

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Cell cycle checkpoint abrogation, especially the inhibition of Chk1 in combination with DNA-damaging treatments, has been proposed as a promising way of sensitizing cancer cells. However, less is known about the possibility to selectively affect tumor cells when they are treated with agents that block DNA synthesis in combination with replication checkpoint inhibitors. Here, we present clear insights in the different responses of tumor and non-transformed cells to the inhibition of DNA replication with hydroxyurea in combination with checkpoint abrogation via inhibition of Ataxia telangiectasia-mutated-(ATM) and Rad3-related/ATM (ATR/ ATM) and Chk1 kinases. Interestingly, we find that nontransformed cell lines activate ATR/ATM-and Chk1-independent pathways in response to replication inhibition to prevent mitotic entry with unreplicated DNA. In contrast, tumor cell lines such as HCT116 and HeLa cells rely entirely on Chk1 activity for a proper response to replication inhibitors. Our results show that p38 is activated in response to hydroxyurea treatment and collaborates with Chk1 to prevent mitotic entry in non-transformed cell lines by maintaining cyclin B1/Cdk1 complexes inactive. Furthermore, DNA replication arrest down-regulates cyclin B1 promoter activity in non-transformed cells, but not in tumor cells in a Chk1-and p38-independent way. Thus, our data show that non-transformed cells present a more robust DNA replication checkpoint response compared with tumor cells that involves activation of the p38 pathway. We show that some of these responses to replication block can be lost in tumor cells, causing a defective checkpoint and providing a rationale for tumor-selective effects of combined therapies. [Cancer Res 2007;67(24):11648-56]

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“…Only the nuclear form of p21 is able to inhibit cell cycle progression (41), while cytoplasmic p21 seems to be a positive modulator of cell survival (7,14). p21 is localized in the cytoplasm during monocytic and neuronal differentiation, where it interacts with the kinases SAP and ASK1 and Rho-kinase (3,45,50).…”

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confidence: 99%

Binding of Calmodulin to the Carboxy-Terminal Region of p21 Induces Nuclear Accumulation via Inhibition of Protein Kinase C-Mediated Phosphorylation of Ser153

Rodríguez–Vilarrupla

Jaumot

Abella

et al. 2005

Molecular and Cellular Biology

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Intracellular localization plays an important role in the functional regulation of the cell cycle inhibitor p21. We have previously shown that calmodulin binds to p21 and that calmodulin is essential for the nuclear accumulation of p21. Here, we analyze the mechanism of this regulation. We show that calmodulin inhibits in vitro phosphorylation of p21 by protein kinase C (PKC) and that this inhibition is dependent upon calmodulin binding to p21. Two-dimensional electrophoresis analysis of cells expressing the p21 wild type or p21S153A, a nonphosphorylatable mutant of p21 at position 153, indicates that Ser153 of p21 is a phosphorylable residue in vivo. Furthermore, Western blot analysis using phospho-Ser153-specific antibodies indicates that Ser153 phosphorylation in vivo is induced when PKC is activated and calmodulin is inhibited. The mutation of Ser153 to aspartate, a pseudophosphorylated residue, inhibits the nuclear accumulation of p21. Finally, whereas wild-type p21 translocates to the cytoplasm after PKC activation in the presence of calmodulin inhibitors, p21 carrying a nonphosphorylatable residue at position 153 remains in the nucleus. We propose that calmodulin binding to p21 prevents its phosphorylation by PKC at Ser153 and consequently allows its nuclear localization. When phosphorylated at Ser153, p21 is located at the cytoplasm and disrupts stress fibers.

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Identification of the nuclear localization signal of p21^cip1 and consequences of its mutation on cell proliferation

Cited by 58 publications

References 25 publications

Neisseria gonorrhoeae infection causes DNA damage and affects the expression of p21, p27 and p53 in non-tumor epithelial cells

Neisseria gonorrhoeae infection causes DNA damage and affects the expression of p21, p27 and p53 in non-tumor epithelial cells

Different S/M Checkpoint Responses of Tumor and Non–Tumor Cell Lines to DNA Replication Inhibition

Binding of Calmodulin to the Carboxy-Terminal Region of p21 Induces Nuclear Accumulation via Inhibition of Protein Kinase C-Mediated Phosphorylation of Ser153

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Identification of the nuclear localization signal of p21cip1 and consequences of its mutation on cell proliferation

Cited by 58 publications

References 25 publications

Neisseria gonorrhoeae infection causes DNA damage and affects the expression of p21, p27 and p53 in non-tumor epithelial cells

Neisseria gonorrhoeae infection causes DNA damage and affects the expression of p21, p27 and p53 in non-tumor epithelial cells

Different S/M Checkpoint Responses of Tumor and Non–Tumor Cell Lines to DNA Replication Inhibition

Binding of Calmodulin to the Carboxy-Terminal Region of p21 Induces Nuclear Accumulation via Inhibition of Protein Kinase C-Mediated Phosphorylation of Ser153

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Identification of the nuclear localization signal of p21^cip1 and consequences of its mutation on cell proliferation