scholarly journals Calcium and S100B Regulation of p53-Dependent Cell Growth Arrest and Apoptosis

1998 ◽  
Vol 18 (7) ◽  
pp. 4272-4281 ◽  
Author(s):  
Christian Scotto ◽  
Jean Christophe Deloulme ◽  
Denis Rousseau ◽  
Edmond Chambaz ◽  
Jacques Baudier
Keyword(s):  
Cell Growth ◽  
Uv Irradiation ◽  
Growth Arrest ◽  
Nuclear Accumulation ◽  
Permissive Temperature ◽  
Wild Type ◽  
Cell Growth Arrest ◽  
Calcium Dependent ◽  
Inhibition Of Growth ◽  
Dependent Cell

ABSTRACT In glial C6 cells constitutively expressing wild-type p53, synthesis of the calcium-binding protein S100B is associated with cell density-dependent inhibition of growth and apoptosis in response to UV irradiation. A functional interaction between S100B and p53 was first demonstrated in p53-negative mouse embryo fibroblasts (MEF cells) by sequential transfection with the S100B and the temperature-sensitive p53Val135 genes. We show that in MEF cells expressing a low level of p53Val135, S100B cooperates with p53Val135 in triggering calcium-dependent cell growth arrest and cell death in response to UV irradiation at the nonpermissive temperature (37.5°C). Calcium-dependent growth arrest of MEF cells expressing S100B correlates with specific nuclear accumulation of the wild-type p53Val135 conformational species. S100B modulation of wild-type p53Val135 nuclear translocation and functions was confirmed with the rat embryo fibroblast (REF) cell line clone 6, which is transformed by oncogenic Ha-ras and overexpression of p53Val135. Ectopic expression of S100B in clone 6 cells restores contact inhibition of growth at 37.5°C, which also correlates with nuclear accumulation of the wild-type p53Val135 conformational species. Moreover, a calcium ionophore mediates a reversible G1 arrest in S100B-expressing REF (S100B-REF) cells at 37.5°C that is phenotypically indistinguishable from p53-mediated G1arrest at the permissive temperature (32°C). S100B-REF cells proceeding from G1 underwent apoptosis in response to UV irradiation. Our data support a model in which calcium signaling and S100B cooperate with the p53 pathways of cell growth inhibition and apoptosis.

scholarly journals Polycomb Group Protein PHF1 Regulates p53-dependent Cell Growth Arrest and Apoptosis

2012 ◽  
Vol 288 (1) ◽  
pp. 529-539 ◽  
Author(s):  
Yang Yang ◽  
Chenji Wang ◽  
Pingzhao Zhang ◽  
Kun Gao ◽  
Dejie Wang ◽  
...  
Keyword(s):  
Cell Growth ◽  
Growth Arrest ◽  
Polycomb Group ◽  
Polycomb Group Protein ◽  
Cell Growth Arrest ◽  
Dependent Cell ◽  
Group Protein

scholarly journals Concerted Regulation of Wild-Type p53 Nuclear Accumulation and Activation by S100B and Calcium-Dependent Protein Kinase C

1999 ◽  
Vol 19 (10) ◽  
pp. 7168-7180 ◽  
Author(s):  
Christian Scotto ◽  
Christian Delphin ◽  
Jean Christophe Deloulme ◽  
Jacques Baudier
Keyword(s):  
Nuclear Translocation ◽  
Growth Arrest ◽  
Nuclear Accumulation ◽  
Temperature Sensitive ◽  
Checkpoint Control ◽  
Wild Type ◽  
Calcium Dependent ◽  
Mouse Embryo Fibroblasts ◽  
Wild Type P53 ◽  
Embryo Fibroblasts

ABSTRACT The calcium ionophore ionomycin cooperates with the S100B protein to rescue a p53-dependent G1 checkpoint control in S100B-expressing mouse embryo fibroblasts and rat embryo fibroblasts (REF cells) which express the temperature-sensitive p53Val135 mutant (C. Scotto, J. C. Deloulme, D. Rousseau, E. Chambaz, and J. Baudier, Mol. Cell. Biol. 18:4272–4281, 1998). We investigated in this study the contributions of S100B and calcium-dependent PKC (cPKC) signalling pathways to the activation of wild-type p53. We first confirmed that S100B expression in mouse embryo fibroblasts enhanced specific nuclear accumulation of wild-type p53. We next demonstrated that wild-type p53 nuclear translocation and accumulation is dependent on cPKC activity. Mutation of the five putative cPKC phosphorylation sites on murine p53 into alanine or aspartic residues had no significant effect on p53 nuclear localization, suggesting that the cPKC effect on p53 nuclear translocation is indirect. A concerted regulation by S100B and cPKC of wild-type p53 nuclear translocation and activation was confirmed with REF cells expressing S100B (S100B-REF cells) overexpressing the temperature-sensitive p53Val135 mutant. Stimulation of S100B-REF cells with the PKC activator phorbol ester phorbol myristate acetate (PMA) promoted specific nuclear translocation of the wild-type p53Val135 species in cells positioned in early G1 phase of the cell cycle. PMA also substituted for ionomycin in the mediating of p53-dependent G1 arrest at the nonpermissive temperature (37.5°C). PMA-dependent growth arrest was linked to the cell apoptosis response to UV irradiation. In contrast, growth arrest mediated by a temperature shift to 32°C protected S100B-REF cells from apoptosis. Our results suggest a model in which calcium signalling, linked with cPKC activation, cooperates with S100B to promote wild-type p53 nuclear translocation in early G1 phase and activation of a p53-dependent G1checkpoint control.

scholarly journals Partial pneumonectomy of telomerase null mice carrying shortened telomeres initiates cell growth arrest resulting in a limited compensatory growth response

2011 ◽  
Vol 300 (6) ◽  
pp. L898-L909 ◽  
Author(s):  
Sha-Ron Jackson ◽  
Jooeun Lee ◽  
Raghava Reddy ◽  
Genevieve N. Williams ◽  
Alexander Kikuchi ◽  
...  
Keyword(s):  
Cell Growth ◽  
Compensatory Growth ◽  
Growth Arrest ◽  
Telomerase Activity ◽  
Lung Growth ◽  
Wild Type ◽  
Term Survival ◽  
Cell Growth Arrest ◽  
Compensatory Lung Growth ◽  
The Impact

Telomerase mutations and significantly shortened chromosomal telomeres have recently been implicated in human lung pathologies. Natural telomere shortening is an inevitable consequence of aging, which is also a risk factor for development of lung disease. However, the impact of shortened telomeres and telomerase dysfunction on the ability of lung cells to respond to significant challenge is still largely unknown. We have previously shown that lungs of late generation, telomerase null B6.Cg- Terc tm1Rdp mice feature alveolar simplification and chronic stress signaling at baseline, a phenocopy of aged lung. To determine the role telomerase plays when the lung is challenged, B6.Cg- Terc tm1Rdp mice carrying shortened telomeres and wild-type controls were subjected to partial pneumonectomy. We found that telomerase activity was strongly induced in alveolar epithelial type 2 cells (AEC2) of the remaining lung immediately following surgery. Eighty-six percent of wild-type animals survived the procedure and exhibited a burst of early compensatory growth marked by upregulation of proliferation, stress response, and DNA repair pathways in AEC2. In B6.Cg- Terc tm1Rdp mice carrying shortened telomeres, response to pneumonectomy was characterized by decreased survival, diminished compensatory lung growth, attenuated distal lung progenitor cell response, persistent DNA damage, and cell growth arrest. Overall, survival correlated strongly with telomere length. We conclude that functional telomerase and properly maintained telomeres play key roles in both long-term survival and the early phase of compensatory lung growth following partial pneumonectomy.

Histone Deacetylase Inhibitors Induce Cell Growth Inhibition and Apoptosis in NPM1-Mutated AML Cells: A Possible Role for Epigenetic Therapies in AML Carrying NPM1 Gene Mutations

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2621-2621
Author(s):  
Ilaria Gionfriddo ◽  
Federica Mezzasoma ◽  
Federica Cecchetti ◽  
Roberta Rossi ◽  
Francesca Strozzini ◽  
...  
Keyword(s):  
Cell Growth ◽  
Cell Line ◽  
Sodium Butyrate ◽  
Growth Arrest ◽  
Gene Mutations ◽  
Caspase 8 ◽  
Trail Receptor ◽  
Wild Type ◽  
Cell Growth Arrest ◽  
Flow Cytometric

Abstract Abstract 2621 Acute myeloid leukemia (AML) carrying nucleophosmin (NPM1) gene mutations account for about one-third of adult AML, show distinctive biological and clinical features and have been included as a provisional entity in the 2008 World Health Organization (WHO) classification of myeloid neoplasms. In spite of the relatively good prognosis of NPM1-mutated AML, there are still cases that show poorer outcome, especially those associated with FLT3-ITD mutation and elderly patient population. Therefore new therapeutic strategies need to be explored. As for other types of cancer, evidence is emerging that, besides the genomic DNA alterations, epigenetic dysregulation may play a role in AML pathogenesis. We investigated the effects of sodium butyrate, a short-chain fatty acid which has long been known to be a histone deacetylase inhibitor (HDACi) able to induce maturation in normal and tumor cells, in cellular models of NPM1-mutated AML in vitro: i) the OCI/AML3 cell line, previously identified as a human AML cell line carrying cytoplasmic mutated NPM1 in the absence of FLT3-ITD; ii) primary AML cells originated from a patient with NPM1-mutated AML bearing FLT3-ITD mutation (MONT1) and propagated as cell line in NOD/SCID mice; and iii) primary AML cells from NPM1-mutated AML patients at diagnosis. In either cell lines or patients' primary AML cells carrying NPM1 mutation, but not in the U937 or OCI/AML2 cell lines (not harboring NPM1 gene mutation) used as control, growth arrest, cell cycle arrest (G0-G1 phase) and pro-apoptotic effects were evident after 24 hrs and marked after 48 hrs of treatment with doses of drug of 0.5–1 mM. No signs of differentiation were evident at morphological and flow cytometric examinations of treated cells. Western blot analysis with specific antibodies showed that levels of either NPM1 mutant or wild-type protein did not appear significantly affected by treatment with sodium butyrate. Interestingly, induction of apoptosis was associated with marked activation of caspase-8, suggesting involvement of the death cell receptors pathway. Indeed, flow cytometric analysis showed 2-fold increased expression of TRAIL-receptor DR5 upon drug treatment at 48 hrs. Moreover, concomitant treatment with a specific caspase-8 inhibitor prevented sodium butyrate induced-cell growth arrest and markedly reduced apoptosis in OCI/AML3 cell line. Derivatives of butyrate, which are capable of acting as HDAC inhibitors, are currently being investigated in clinical trials; preliminary results suggest their potential applicability in cancer treatment. Here we investigated the effect of panobinostat (LBH589), a pan HDACi, in human AML cells lines and show results similar to those observed upon sodium butyrate treatment in OCI/AML3 cells. In particular, we show that panobinostat induces dose-dependent cell growth arrest, with G0-G1 block, associated with p21 protein induction, and apoptosis, associated with TRAIL-receptor DR5 upregulation and activation of caspase 8, in AML cells harboring NPM1 gene mutation. However, unlike what was observed with sodium butyrate, panobinostat induced also dowregulation of NPM1 mutant (and to a lesser extent, wild type) protein. Mechanisms underlying this phenomenon are under investigation. In particular, the possible role of acetylation of the heat shock protein Hsp90 (as a consequence of panobinostat-mediated HDAC6 inhibition) with disruption of its chaperone functions followed by instability of its client proteins, including cytoplasmic NPM1, is explored. Disclosures: Falini: Xenomics: Patents & Royalties.

scholarly journals Deoxyinosine triphosphate induces MLH1/PMS2- and p53-dependent cell growth arrest and DNA instability in mammalian cells

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Yasuto Yoneshima ◽  
Nona Abolhassani ◽  
Teruaki Iyama ◽  
Kunihiko Sakumi ◽  
Naoko Shiomi ◽  
...  
Keyword(s):  
Cell Growth ◽  
Mammalian Cells ◽  
Growth Arrest ◽  
Cell Growth Arrest ◽  
Dna Instability ◽  
Dependent Cell

scholarly journals TGF-β-dependent Cell Growth Arrest and Apoptosis

BMB Reports ◽  
2002 ◽  
Vol 35 (1) ◽  
pp. 47-53 ◽  
Author(s):  
Kwang-Youl Lee ◽  
Suk-Chul Bae
Keyword(s):  
Cell Growth ◽  
Growth Arrest ◽  
Cell Growth Arrest ◽  
Dependent Cell
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