The p38-Mediated Stress-Activated Checkpoint: A Rapid Response System for Delaying Progression through Antephase and Entry into Mitosis

Mikhailov, Alexei; Shinohara, Mio; Rieder, Conly L.

doi:10.4161/cc.4.1.1357

Cited by 100 publications

(81 citation statements)

References 47 publications

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“…The immediate and global histone hypo-acetylation triggered by p300 HAT inactivation, promoting the formation of heterochomatin alters the replication timing marks, leading to a doubling of S-phase length. Although not related to DDR activation, these alterations challenging chromosome condensation are likely to be sensed as a sudden onset of stress, such as is observed in osmotic shock or hypothermia 39 . A rapid response system, that does not require transcription or translation could then quickly trigger a block of the cell cycle in G2/M, involving Cdc25B 40 .…”

Section: Resultsmentioning

confidence: 99%

p53 and p16INK4A independent induction of senescence by chromatin-dependent alteration of S-phase progression

et al. 2011

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senescence is triggered by various cellular stresses that result in genomic lesions and DnA damage response activation. However, the role of chromatin and DnA replication in senescence induction remains elusive. Here we show that downregulation of p300 histone acetyltransferase activity induces senescence by a mechanism that is independent of the activation of p53, p21 CIP1 and p16 InK4A . This inhibition leads to a global H3, H4 hypoacetylation, initiating senescence-associated heterochromatic foci formation during s phase, together with a global decrease in replication fork velocity, and alteration of DnA replication timing. This replicative stress occurs without DnA damage and checkpoint activation, but results in a robust G2/m cell cycle arrest, within only one cell cycle. These results provide new insights into the control of s-phase progression by p300, and identify an unexpected chromatindependent alternative mechanism for senescence induction, which could possibly be exploited to treat cancer by senescence induction without generating further DnA damage.

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Section: Resultsmentioning

confidence: 99%

p53 and p16INK4A independent induction of senescence by chromatin-dependent alteration of S-phase progression

et al. 2011

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“…p38 is activated after treatment with different genotoxic stresses (Mikhailov et al, 2005) and contributes to IGF-I-mediated rescue of UV-damaged cells (Heron-Milhavet et al, 2001). The IGF-IR has also been shown to activate DNA repair pathways via the ataxia telangiectasia mutated (ATM) kinase (Macaulay et al, 2001;Trojanek et al, 2003;Yang et al, 2005).…”

Section: Resultsmentioning

confidence: 99%

PBK/TOPK promotes tumour cell proliferation through p38 MAPK activity and regulation of the DNA damage response

2006

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The contribution of the insulin-like growth-factor-I receptor (IGF-IR) to tumour progression is well documented. To identify new mediators of IGF-IR function in cancer, we recently isolated genes differentially expressed in cells overexpressing the IGF-IR. Among these was the serine/threonine kinase PBK/TOPK (PDZ-binding kinase/T-LAK cell-originated protein kinase), previously associated with highly proliferative cells and tissues. Here, we show that PBK is expressed at high levels in tumour cell lines compared with non-transformed cells. IGF-I could induce PBK expression only in transformed cells, whereas epidermal growth factor could induce PBK in non-transformed MCF-10A breast epithelial cells. Suppression of PBK expression using small interfering RNA did not prevent progression through the cell cycle, but caused decreased proliferation over time in culture, and reduced clonogenic growth in soft agarose. PBK knockdown impaired p38 activation after long-term stimulation with different growth factors and reduced DU145 cells motility. Suppressed PBK expression also resulted in an impaired response to DNA damage that was evident by the decreased generation of c-H2AX, increased DNA damage and decreased cell survival. Taken together, the data indicate that PBK is necessary for appropriate activation and function of the p38 pathway by growth factors. Thus, enhanced expression of PBK may facilitate tumour growth by mediating p38 activation and by helping cells to overcome DNA damage.

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“…Upon checkpoint activation, early prophase cells transiently return to a late G2 state (Matsusaka and Pines, 2004;Mikhailov et al, 2004). The ubiquitin ligase Chfr (Checkpoint protein with FHA and RING finger domain) was identified as a crucial component of this checkpoint in specific response to microtubule depolymerization with nocodazole (Scolnick and Halazonetis, 2000).…”

Section: Introductionmentioning

confidence: 99%

Chfr interacts and colocalizes with TCTP to the mitotic spindle

et al. 2008

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Chfr is a checkpoint protein that plays an important function in cell cycle progression and tumor suppression, although its exact role and regulation are unclear. Previous studies have utilized overexpression of Chfr to determine the signaling pathway of this protein in vivo. In this study, we demonstrate, by using three different antibodies against Chfr, that the endogenous and highly overexpressed ectopic Chfr protein is localized and regulated differently in cells. Endogenous and lowly expressed ectopic Chfr are cytoplasmic and localize to the spindle during mitosis. Higher expression of ectopic Chfr correlates with a shift in the localization of this protein to the nucleus/PML bodies, and with a block of cell proliferation. In addition, endogenous and lowly expressed ectopic Chfr is stable throughout the cell cycle, whereas when highly expressed, ectopic Chfr is actively degraded during S-G2/ M phases in an autoubiquitination and proteasome-dependent manner. A two-hybrid screen identified TCTP as a possible Chfr-interacting partner. Biochemical analysis with the endogenous proteins confirmed this interaction and identified b-tubulin as an additional partner for Chfr, supporting the mitotic spindle localization of Chfr. The Chfr-TCTP interaction was stable throughout the cell cycle, but it could be diminished by the complete depolymerization of the microtubules, providing a possible mechanism where Chfr could be the sensor that detects microtubule disruption and then activates the prophase checkpoint.

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The p38-Mediated Stress-Activated Checkpoint: A Rapid Response System for Delaying Progression through Antephase and Entry into Mitosis

Cited by 100 publications

References 47 publications

p53 and p16INK4A independent induction of senescence by chromatin-dependent alteration of S-phase progression

p53 and p16INK4A independent induction of senescence by chromatin-dependent alteration of S-phase progression

PBK/TOPK promotes tumour cell proliferation through p38 MAPK activity and regulation of the DNA damage response

Chfr interacts and colocalizes with TCTP to the mitotic spindle

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