scholarly journals Complementation by wild-type p53 of interleukin-6 effects on M1 cells: induction of cell cycle exit and cooperativity with c-myc suppression.

1993 ◽  
Vol 13 (12) ◽  
pp. 7942-7952 ◽  
Author(s):  
N Levy ◽  
E Yonish-Rouach ◽  
M Oren ◽  
A Kimchi
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Cell Cycle Arrest ◽  
Interleukin 6 ◽  
Quiescent State ◽  
Permissive Temperature ◽  
Wild Type ◽  
Antiproliferative Effects ◽  
Cycle Arrest ◽  
Wild Type P53

Stable transfection of M1 myeloid leukemia cells with a temperature-sensitive mutant of p53 results in two phenomena that are manifested exclusively at the permissive temperature. On one hand, activation of wild-type p53 by the temperature shift induced an apoptotic type of cell death which could be inhibited by interleukin-6 (IL-6) (E. Yonish-Rouach, D. Resnitzky, J. Lotem, L. Sachs, A. Kimchi, and M. Oren, Nature 352:345-347, 1991). On the other hand, as reported in this work, activated p53 complemented the antiproliferative effects of IL-6 in M1 cells. A shift to the permissive temperature concomitant with or early after IL-6 treatment imposed a novel pattern of cell cycle arrest in which about 95% of the cells were retained within a G0-like quiescent state. This phase was characterized by 2N DNA content and low RNA and protein content. On the molecular level, activation of wild-type p53 transrepressed the c-myc gene but not the cyclin A, D1, or D2 gene, which are all independently suppressed by IL-6 in M1 cells. To further analyze whether c-myc inhibition mediates or complements p53 effects, the p53-transfected M1 cells were infected with a retroviral vector expressing deregulated c-myc, refractory to p53 or IL-6 action. It was found that the process of cell death was not interrupted at all in these M1 c-myc-p53 double transfectants, suggesting that the transrepression of c-myc is not a major obligatory event mediating p53-induced cell death. In addition, some of the antiproliferative effects of activated p53, manifested in the presence of IL-6, could still be transmitted in the background of constitutive c-myc. Yet the context of deregulated c-myc interfered with the final accumulation of cells within a G0-like phase, suggesting complementary interactions between the outcome of p53 activation and of c-myc suppression in the control of cell cycle arrest.

Complementation by wild-type p53 of interleukin-6 effects on M1 cells: induction of cell cycle exit and cooperativity with c-myc suppression

1993 ◽  
Vol 13 (12) ◽  
pp. 7942-7952
Author(s):  
N Levy ◽  
E Yonish-Rouach ◽  
M Oren ◽  
A Kimchi
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Cell Cycle Arrest ◽  
Interleukin 6 ◽  
Quiescent State ◽  
Permissive Temperature ◽  
Wild Type ◽  
Antiproliferative Effects ◽  
Cycle Arrest ◽  
Wild Type P53

Stable transfection of M1 myeloid leukemia cells with a temperature-sensitive mutant of p53 results in two phenomena that are manifested exclusively at the permissive temperature. On one hand, activation of wild-type p53 by the temperature shift induced an apoptotic type of cell death which could be inhibited by interleukin-6 (IL-6) (E. Yonish-Rouach, D. Resnitzky, J. Lotem, L. Sachs, A. Kimchi, and M. Oren, Nature 352:345-347, 1991). On the other hand, as reported in this work, activated p53 complemented the antiproliferative effects of IL-6 in M1 cells. A shift to the permissive temperature concomitant with or early after IL-6 treatment imposed a novel pattern of cell cycle arrest in which about 95% of the cells were retained within a G0-like quiescent state. This phase was characterized by 2N DNA content and low RNA and protein content. On the molecular level, activation of wild-type p53 transrepressed the c-myc gene but not the cyclin A, D1, or D2 gene, which are all independently suppressed by IL-6 in M1 cells. To further analyze whether c-myc inhibition mediates or complements p53 effects, the p53-transfected M1 cells were infected with a retroviral vector expressing deregulated c-myc, refractory to p53 or IL-6 action. It was found that the process of cell death was not interrupted at all in these M1 c-myc-p53 double transfectants, suggesting that the transrepression of c-myc is not a major obligatory event mediating p53-induced cell death. In addition, some of the antiproliferative effects of activated p53, manifested in the presence of IL-6, could still be transmitted in the background of constitutive c-myc. Yet the context of deregulated c-myc interfered with the final accumulation of cells within a G0-like phase, suggesting complementary interactions between the outcome of p53 activation and of c-myc suppression in the control of cell cycle arrest.

scholarly journals Co-expression of murine double minute 2 siRNA and wild-type p53 induces G1 cell cycle arrest in H1299 cells

2017 ◽  
Vol 16 (6) ◽  
pp. 9137-9142
Author(s):  
Long Liu ◽  
Ping Zhang ◽  
Hua Guo ◽  
Xinyu Tang ◽  
Lianqin Liu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Wild Type ◽  
Cycle Arrest ◽  
Double Minute ◽  
G1 Cell Cycle Arrest ◽  
Murine Double Minute ◽  
Wild Type P53

scholarly journals Enhanced wild-type p53 expression by small activating RNA dsP53-285 induces cell cycle arrest and apoptosis in pheochromocytoma cell line PC12

2017 ◽  
Vol 38 (5) ◽  
pp. 3160-3166 ◽  
Author(s):  
Dengqiang Lin ◽  
Li Meng ◽  
Feifei Xu ◽  
Jianpo Lian ◽  
Yunze Xu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Line ◽  
Wild Type ◽  
P53 Expression ◽  
Cycle Arrest ◽  
Pheochromocytoma Cell ◽  
Wild Type P53

Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53

Cell ◽  
1992 ◽  
Vol 70 (6) ◽  
pp. 923-935 ◽  
Author(s):  
Laura R. Livingstone ◽  
Alicia White ◽  
Jason Sprouse ◽  
Elizabeth Livanos ◽  
Tyler Jacks ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Gene Amplification ◽  
Wild Type ◽  
Cycle Arrest ◽  
Wild Type P53 ◽  
Altered Cell

Inhibition of p53-MDM2 Interaction by Small-Molecule Antagonist of MDM2 Effectively Induces Apoptosis in Leukemias.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2536-2536
Author(s):  
Kensuke Kojima ◽  
Marina Konopleva ◽  
Masato Shikami ◽  
Maria Cabreira-Hansen ◽  
C. Ellen Jackson ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Annexin V ◽  
Cell Number ◽  
Leukemia Cells ◽  
P53 Mutations ◽  
Wild Type ◽  
Cycle Arrest ◽  
Wild Type P53 ◽  
Induced Apoptosis

Abstract Alteration of the p53 gene is one of the most frequent events in human tumorigenesis and about 50% of all solid tumors have been reported to carry p53 mutations. The inactivation of p53 in cancer has been associated with poor survival, refractory disease and chemoresistance. p53 mutations rarely occur in hematopoietic malignancies. Instead, MDM2 which is a principal cellular antagonist of p53, is overexpressed in the majority of leukemias. Recently, potent and selective small-molecule antagonists of MDM2, Nutlins, have been identified (Science303:844–888, 2004). Nutlins bind MDM2 in the p53-binding pocket and activate the p53 pathway in human cancer cells with wild-type p53, leading to cell cycle arrest, apoptosis, and growth inhibition of human tumor xenografts in nude mice. In this study, we investigated the potential antileukemic activity of the MDM2 antagonist. Treatment of wild-type p53 OCI-AML-3 cells with 5 μM of an active compound (Nutlin-3a) induced cell cycle arrest and apoptosis as evidenced by flow-cytometric analysis (51% reduction of S-phase at 12 h, 27% sub-G1 DNA content and 57% Annexin V positivity at 48 h). Similar proapoptotic effects were observed in MOLM-13 cells which have wild-type p53, but not in p53-null (HL-60 and U937) or mutant p53 (Raji, Jurkat and NB-4) cells. Nutlin-3a induced apoptosis in a dose- and time-dependent manner, and induced maximal effect on cell cycle arrest at 1 μM. Western blot analysis showed that in OCI-AML-3 cells, wild-type p53 accumulated at 1 h after exposure to Nutlin-3a. Increased levels of MDM2, p21 and Noxa proteins were observed at 1 to 3h. This resulted in cleavage of caspase-9 followed by cleavage of caspase-3. A pharmacologic interaction study between MDM2 inhibitor and Ara-C using a fixed-ratio (1:1) experimental design showed highly synergistic cell growth inhibition (CI = 0.44) and induction of apoptosis (CI = 0.83) in OCI-AML-3 cells. Initial studies conducted in primary leukemia cells demonstrated that Nutlin-3a induced apoptosis in 4 of 5 AML samples tested (68–97% Annexin V induction and 65–93% cell number reduction) and 2 CLL samples (>50% Annexin V induction and 37% and 58% cell number reduction). Since MDM2 protein is overexpressed and p53 is not mutated in the majority of primary leukemia cells, this approach may have therapeutic utility in leukemias.

The MDM2 Antagonist Nutlin-3 Is Effective to Aggressive NK-Cell Neoplasms with Wild Type p53 in Hypoxia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4999-4999
Author(s):  
Yoko Tabe ◽  
Yasushi Isobe ◽  
Koichi Sugimoto ◽  
Linhua Jin ◽  
Kazuo Oshimi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Nk Cell ◽  
Apoptotic Cell ◽  
Annexin V ◽  
Wild Type ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest

Abstract Abstract 4999 Natural killer (NK) cell neoplasms, including extranodal NK/T-cell lymphoma, nasal type (ENKL) and aggressive NK cell leukemia (ANKL), show a highly aggressive clinical course with poor response to chemotherapy, and new treatment approaches are urgently needed to improve cure rates. Patients with NK cell neoplasms cluster in Asia and Latin American countries, and the frequency of p53 mutations has been reported to be various by district. We have demonstrated that MDM2 protein was overexpressed in aggressive subclasses of NK cell neoplasms (Sugimoto et al. Jap J Cancer Res. 2002), which suggests that wild-type p53 expressing malignant NK cells may be a good candidate for biologic therapies that abrogate MDM2-p53 interactions and lead to cell death. Nutlin-3 is a small-molecule antagonist of MDM2 that efficiently blocks the MDM2-p53 interaction. In this study, we investigated the effects of nutlin-3 in 3 cell lines of ENKL and ANKL with known p53 mutation status (wt-p53: NK-YS, HANK-1; mt-p53: KHYG-1). Since aggressive NK-cell neoplasms arise in hypoxic environments and usually show an angiodestructive-infiltration pattern resulting in the tissue necrosis, we tried to assess the anti-proliferative effects and molecular mechanisms of nutlin-3 in the hypoxic condition. For hypoxia experiments, cells were cultured under 1.0% O2 for at least 14 days to assure their continuous proliferation and survival. Under hypoxia, more cells were positive to Annexin V than in normoxia, indicating that hypoxic conditions promote apoptosis in NK cell neoplasms. Nutlin-3 treatment in normoxia resulted in a reduction of cell proliferation with G0/G1 cell cycle arrest in a time and concentration-dependent manner in wt-p53 cells (IC50 at 48 hrs; 3.2 μM for NK-YS and 5.0 μM for HANK-1, MTT test). In hypoxia, nutlin-3 further enhanced cell growth inhibition and G0/G1 cell cycle arrest. An increase in the specific apoptosis (sub G1 and annexin V positivity) by nutlin-3 was observed with similar level between normoxia and hypoxia. The mt-p53 KHYG-1 cells demonstrated neither cell cycle arrest nor increase in the apoptotic cell fraction after nutlin-3 treatment. In the wt-p53 NK-YS and HANK-1 cells, nutlin-3 treatment increased the cellular levels of p53, and p53 dependent proteins including p21, MDM2 itself and the proapoptotic BH3-only proteins Noxa and Puma followed by the activation of caspase-9 and caspase-3 regardless of foxygen level. We observed no significant increase in the p53 targets in the mt-p53 overexpressing KHYG-1 cells. L-asparaginase has been demonstrated to induce apoptosis in aggressive NK cell neopplasms. To determine if inhibition of the TP53-MDM2 interaction by nutlin-3 in NK cell neoplasms might potentiate the effects of L-asparaginase, we assessed the effect of combining the two drugs. However, L-asparaginase induced apoptosis only in NK-YS cells, and no synergistic anti-proliferative effect was observed in any of the cell lines analyzed. These findings demonstrate that nutlin-3 successfully activates wt-p53 in NK cell neoplasms leading to the upregulation of traditional targets such as p21 and proapoptotic proteins including Noxa and Puma, and result in apoptotic cell death regardless of oxygen concentration. The data suggest that p53 activators such as nutlin-3 may be considerable for selected patients with wt-p53 NK cell neoplasms. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Marine Invertebrate Extracts Induce Colon Cancer Cell Death via ROS-Mediated DNA Oxidative Damage and Mitochondrial Impairment

Biomolecules ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 771 ◽  
Author(s):  
Verónica Ruiz-Torres ◽  
Celia Rodríguez-Pérez ◽  
María Herranz-López ◽  
Beatriz Martín-García ◽  
Ana-María Gómez-Caravaca ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Colon Cancer ◽  
Dna Damage ◽  
Cell Death ◽  
Cell Cycle Arrest ◽  
Colon Cancer Cell ◽  
Mitochondrial Depolarization ◽  
Antiproliferative Effects ◽  
Cycle Arrest ◽  
Ros Accumulation

Marine compounds are a potential source of new anticancer drugs. In this study, the antiproliferative effects of 20 invertebrate marine extracts on three colon cancer cell models (HGUE-C-1, HT-29, and SW-480) were evaluated. Extracts from two nudibranchs (Phyllidia varicosa, NA and Dolabella auricularia, NB), a holothurian (Pseudocol ochirus violaceus, PS), and a soft coral (Carotalcyon sp., CR) were selected due to their potent cytotoxic capacities. The four marine extracts exhibited strong antiproliferative effects and induced cell cycle arrest at the G2/M transition, which evolved into early apoptosis in the case of the CR, NA, and NB extracts and necrotic cell death in the case of the PS extract. All the extracts induced, to some extent, intracellular ROS accumulation, mitochondrial depolarization, caspase activation, and DNA damage. The compositions of the four extracts were fully characterized via HPLC-ESI-TOF-MS analysis, which identified up to 98 compounds. We propose that, among the most abundant compounds identified in each extract, diterpenes, steroids, and sesqui- and seterterpenes (CR); cembranolides (PS); diterpenes, polyketides, and indole terpenes (NA); and porphyrin, drimenyl cyclohexanone, and polar steroids (NB) might be candidates for the observed activity. We postulate that reactive oxygen species (ROS) accumulation is responsible for the subsequent DNA damage, mitochondrial depolarization, and cell cycle arrest, ultimately inducing cell death by either apoptosis or necrosis.

Ceragenin CSA-13 induces cell cycle arrest and antiproliferative effects in wild-type and p53 null mutant HCT116 colon cancer cells

2013 ◽  
Vol 24 (8) ◽  
pp. 826-834 ◽  
Author(s):  
Kengo Kuroda ◽  
Tomokazu Fukuda ◽  
Kazuhiko Okumura ◽  
Hiroshi Yoneyama ◽  
Hiroshi Isogai ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Colon Cancer ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Null Mutant ◽  
Colon Cancer Cells ◽  
Wild Type ◽  
Antiproliferative Effects ◽  
Cycle Arrest

The role of p53 and cell death by apoptosis and necrosis in 4-hydroperoxycyclophosphamide-induced limb malformations

Development ◽  
1998 ◽  
Vol 125 (16) ◽  
pp. 3225-3234
Author(s):  
S.A. Moallem ◽  
B.F. Hales
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Drug Treatment ◽  
Cell Cycle Arrest ◽  
Wild Type ◽  
Cycle Arrest ◽  
Limb Malformations ◽  
Apoptosis And Necrosis

The exposure of embryonic murine limbs in vitro to an activated analog of cyclophosphamide, 4-hydroperoxycyclophosphamide (4OOH-CPA), induced limb malformations and apoptosis. The purpose of this study was to investigate the role of the tumor suppressor/cell cycle checkpoint gene, p53, and of cell cycle arrest in the response of the limbs to cyclophosphamide. Limbs, excised on day 12 of gestation from wild-type, heterozygous or homozygous p53-knockout transgenic murine embryos, were treated with vehicle (water) or 4OOH-CPA (0.3, 1.0 or 3.0 microgram/ml) and cultured for 6 days. Exposure of wild-type (+/+) limbs to 4OOH-CPA resulted in limb malformations, and reduced limb areas and developmental scores. The homozygous (−/−) limbs were dramatically more sensitive to the effects of 4OOH-CPA, as assessed by limb morphology, area and score. Heterozygous limbs exposed to the drug were intermediate for each parameter. Apoptosis, as assessed by the formation of a DNA ladder, was increased in drug-exposed wild-type limbs, but not in the drug-exposed homozygous limbs. Light and electron microscopy examination of the limbs revealed that drug treatment of wild-type limbs induced the morphological changes typical of apoptosis, particularly in the interdigital regions. In contrast, there was no evidence of apoptosis in homozygous limbs exposed to 4-OOH-CPA; morphological characteristics of necrosis such as cell membrane breakdown, mitochondrial swelling and cellular disintegration were evident throughout these limbs. Heterozygous limbs had cells dying with the characteristics of both apoptosis and necrosis. Fragments of poly(ADP-ribose) polymerase characteristic of necrosis predominated in the drug-treated heterozygous and homozygous limbs. 4-OOH-CPA-treatment of limbs from wild-type embryos led to arrest of the cell cycle at the G1/S phase. No cell cycle arrest was observed after drug treatment of homozygous limbs, in which populations of cells in S and G2/M phases, as well as a population of sub G1 cells, were found. Thus, the presence of p53 and of p53-dependent apoptosis protect organogenesis-stage limbs from insult with a teratogen. The absence of p53 may decrease DNA repair capacity and contribute to the accumulation of DNA damage in limb cells and their daughter cells; the failure of apoptosis to eliminate cells with DNA damage may result in increased cell death by necrosis and major limb malformations.

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