Wild-type p53 gene transfer resulted in cell cycle arrest, but not apoptosis of newly established human malignant fibrous histiocytoma cell line.

1999 ◽  
Author(s):  
K Endo ◽  
T Sakatani ◽  
M Watanabe ◽  
H Yoshida ◽  
E Nanba ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Gene Transfer ◽  
Cell Cycle Arrest ◽  
Cell Line ◽  
Malignant Fibrous Histiocytoma ◽  
Fibrous Histiocytoma ◽  
P53 Gene ◽  
Wild Type ◽  
Cycle Arrest ◽  
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

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 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.

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.

MDM2, MDMX, and p73 regulate cell-cycle progression in the absence of wild-type p53

2021 ◽  
Vol 118 (44) ◽  
pp. e2102420118
Author(s):  
Alyssa M. Klein ◽  
Lynn Biderman ◽  
David Tong ◽  
Bita Alaghebandan ◽  
Sakina A. Plumber ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Cycle Progression ◽  
Family Members ◽  
Wild Type ◽  
Cycle Progression ◽  
Cycle Arrest ◽  
Double Minute ◽  
Murine Double Minute ◽  
Wild Type P53

The p53 tumor suppressor protein, known to be critically important in several processes including cell-cycle arrest and apoptosis, is highly regulated by multiple mechanisms, most certifiably the Murine Double Minute 2–Murine Double Minute X (MDM2–MDMX) heterodimer. The role of MDM2–MDMX in cell-cycle regulation through inhibition of p53 has been well established. Here we report that in cells either lacking p53 or expressing certain tumor-derived mutant forms of p53, loss of endogenous MDM2 or MDMX, or inhibition of E3 ligase activity of the heterocomplex, causes cell-cycle arrest. This arrest is correlated with a reduction in E2F1, E2F3, and p73 levels. Remarkably, direct ablation of endogenous p73 produces a similar effect on the cell cycle and the expression of certain E2F family members at both protein and messenger RNA levels. These data suggest that MDM2 and MDMX, working at least in part as a heterocomplex, may play a p53-independent role in maintaining cell-cycle progression by promoting the activity of E2F family members as well as p73, making them a potential target of interest in cancers lacking wild-type p53.

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.

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