p53 regulates a G
            <sub>2</sub>
            checkpoint through cyclin B1

Innocente, Steven A.; Abrahamson, John; Cogswell, John; Lee, Jonathan M.

doi:10.1073/pnas.96.5.2147

Cited by 404 publications

(300 citation statements)

References 40 publications

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“…Adp53 infection strongly reduced the proliferation rate of the Ras-transformed cells (Figure 2a), with a reduction of BrdU incorporation ( Figure 2b) and a preferential accumulation in the G2/M phase of the cell cycle (Figure 2c) as reported in other systems, 19 without induction of apoptosis (Figure 2c; o5% of TUNEL-positive cells in both dl70.3 control virus-and Adp53-infected cells). TUNEL and/or viability controls, to ensure the absence of cell death, were performed in each of the following experiments.…”

Section: P53-induced Growth Arrest Of V-ha-rastransformed Cells Is Assupporting

confidence: 71%

p53 can inhibit cell proliferation through caspase-mediated cleavage of ERK2/MAPK

Marchetti

Cecchinelli²,

D'Angelo³

et al. 2004

Cell Death Differ

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Stimulation of the Ras/MAPK cascade can either activate p53 and promote replicative senescence and apoptosis, or degrade p53 and promote cell survival. Here we show that p53 can directly counteract the Ras/MAPK signaling by inactivating ERK2/MAPK. This inactivation is due to a caspase cleavage of the ERK2 protein and contributes to p53-mediated growth arrest. We found that in Ras-transformed cells, growth arrest induced by p53, but not p21 Waf1 , is associated with a strong reduction in ERK2 activity, phosphorylation, and protein half-life, and with the appearance of caspase activity. Likewise, DNA damage-induced cell cycle arrest correlates with p53-dependent ERK2 downregulation and caspase activation. Furthermore, caspase inhibitors or expression of a caspase-resistant ERK2 mutant interfere with ERK2 cleavage and restore proliferation in the presence of p53 activation, indicating that caspase-mediated ERK2 degradation contributes to p53-induced growth arrest. These findings strongly point to ERK2 as a novel p53 target in growth suppression.

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Section: P53-induced Growth Arrest Of V-ha-rastransformed Cells Is Assupporting

confidence: 71%

p53 can inhibit cell proliferation through caspase-mediated cleavage of ERK2/MAPK

Marchetti

Cecchinelli²,

D'Angelo³

et al. 2004

Cell Death Differ

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“…And indeed, loss of p53 as well as loss of its downstream target p21 re-established drug synergism in (colon cancer-derived) HCT116 cells 22 (Supplementary Figure S1H), accompanied by increased γH2AX levels and accumulation of mitotically arrested cells (Supplementary Figures S1I and S1J). Similarly, shRNA-mediated depletion of wild-type p53 in the ovarian cancer-derived cell line A2780 led to increased levels of the G2 checkpoint regulator cyclin B1, 23 as well as decreased levels of carboplatin-induced DDB2 (Supplementary Figure S1L), a p53-inducible gene product involved in mediating carboplatin resistance. 24 In conclusion, ganetespib and platinum act in a synergistic manner to induce death in the majority of ovarian carcinoma cells but not in non-transformed and/or p53-proficient cells.…”

Section: Untransformed Cellsmentioning

confidence: 96%

Strong antitumor synergy between DNA crosslinking and HSP90 inhibition causes massive premitotic DNA fragmentation in ovarian cancer cells

et al. 2016

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All current regimens for treating ovarian cancer center around carboplatin as standard first line. The HSP90 inhibitor ganetespib is currently being assessed in advanced clinical oncology trials. Thus, we tested the combined effects of ganetespib and carboplatin on a panel of 15 human ovarian cancer lines. Strikingly, the two drugs strongly synergized in cytotoxicity in tumor cells lacking wild-type p53. Mechanistically, ganetespib and carboplatin in combination, but not individually, induced persistent DNA damage causing massive global chromosome fragmentation. Live-cell microscopy revealed chromosome fragmentation occurring to a dramatic degree when cells condensed their chromatin in preparation for mitosis, followed by cell death in mitosis or upon aberrant exit from mitosis. HSP90 inhibition caused the rapid decay of key components of the Fanconi anemia pathway required for repair of carboplatin-induced interstrand crosslinks (ICLs), as well as of cell cycle checkpoint mediators. Overexpressing FancA rescued the DNA damage induced by the drug combination, indicating that FancA is indeed a key client of Hsp90 that enables cancer cell survival in the presence of ICLs. Conversely, depletion of nuclease DNA2 prevented chromosomal fragmentation, pointing to an imbalance of defective repair in the face of uncontrolled nuclease activity as mechanistic basis for the observed premitotic DNA fragmentation. Importantly, the drug combination induced robust antitumor activity in xenograft models, again accompanied with depletion of FancA. In sum, our findings indicate that ganetespib strongly potentiates the antitumor efficacy of carboplatin by causing combined inhibition of DNA repair and cell cycle control mechanisms, thus triggering global chromosome disruption, aberrant mitosis and cell death. 6 This provides a strong rationale for HSP90 inhibitors in cancer therapy 7 and raises the possibility that HSP90 inhibitors can be used in combination with DNAdamaging chemotherapeutics. 8 Ovarian cancer is among the most common gynecological tumor types and carries the worst prognosis. HSP90 is highly expressed in advanced ovarian carcinoma 9 and thus constitutes a potential therapeutic drug target. 10 In support, HSP90 inhibitors were found effective against ovarian cancer in preclinical models, 11-14 alone or in combination with conventional chemotherapy. 15,16 Carboplatin is the key component of all current first-line therapies for ovarian carcinoma. However, while initially often responding with regression, most tumors relapse and develop resistance within less than a year. 17,18 Like other platinum compounds, carboplatin acts by forming crosslinks within DNA. 17 Platinum compounds form intrastrand DNA lesions but also interstrand crosslinks (ICLs) by covalently linking opposite DNA strands. Such ICLs represent major obstacles to the DNA replication fork 19 and are therefore considered the principal toxic lesion of carboplatin's mode of action. The ICLs can only be removed by a sophisticated DNA repair systemthe Fanconi ...

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“…For example, p130 was shown to interact with E2F4 and repress the Cdk1 promoter when p53 was overexpressed in the absence of any DNA damage . Overexpression of p53 regulates the extent of the arrest via Cyclin B1 repression (Innocente et al, 1999). However, the arrest in C4-2 cells can occur independently of Cyclin B1 and its associated kinase activities, as our investigations indicated that following irradiation, there are minimal changes in the p53-deficient DN-p53-C4-2 cells while there are dramatically downregulated Cyclin B1 levels in C4-2 cells (S Ray et al, unpublished data).…”

Section: Discussionmentioning

confidence: 67%

E2F4 regulates a stable G2 arrest response to genotoxic stress in prostate carcinoma

et al. 2006

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The retinoblastoma (pRB) family proteins regulate the E2F transcription factors; their complexes regulate critical transitions through the cell cycle. The function of these pRB family/E2F complexes, which includes p130/ E2F4, in response to genotoxic agents, is not well understood. We investigated the role of E2F4 in the genotoxic stress response. Following radiation treatment, E2F4 colocalized with p130 in the nucleus during a radiation-induced stable G 2 -phase arrest. Arrested cells had significantly decreased expression of Cyclins A2 and B1 and decreased phosphorylation of mitotic protein monoclonal-2 (MPM-2) mitotic proteins. Small interference RNA (siRNA)-mediated knockdown of E2F4 sensitized cells to subsequent irradiation, resulting in enhanced cellular DNA damage and cell death, as determined by caspase activation and decreased clonogenic cell survival. Downstream E2F4 targets potentially involved in the progression from G 2 into M phase were identified by oligonucleotide microarray expression profiling. Chromatin immunoprecipitation localized E2F4 at promoter regions of the Bub3 and Pttg1 mitotic genes following irradiation, which were among the downregulated genes identified by the microarray. These data suggest that in response to radiation, E2F4 becomes active in the nucleus, enforces a stable G 2 arrest by target gene repression, and thus provides increased cell survival ability by minimizing propagation of cells that have irreparable DNA damage.

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p53 regulates a G ₂ checkpoint through cyclin B1

Cited by 404 publications

References 40 publications

p53 can inhibit cell proliferation through caspase-mediated cleavage of ERK2/MAPK

p53 can inhibit cell proliferation through caspase-mediated cleavage of ERK2/MAPK

Strong antitumor synergy between DNA crosslinking and HSP90 inhibition causes massive premitotic DNA fragmentation in ovarian cancer cells

E2F4 regulates a stable G2 arrest response to genotoxic stress in prostate carcinoma

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p53 regulates a G 2 checkpoint through cyclin B1

Cited by 404 publications

References 40 publications

p53 can inhibit cell proliferation through caspase-mediated cleavage of ERK2/MAPK

p53 can inhibit cell proliferation through caspase-mediated cleavage of ERK2/MAPK

Strong antitumor synergy between DNA crosslinking and HSP90 inhibition causes massive premitotic DNA fragmentation in ovarian cancer cells

E2F4 regulates a stable G2 arrest response to genotoxic stress in prostate carcinoma

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p53 regulates a G ₂ checkpoint through cyclin B1