scholarly journals p53-mediated cell death: relationship to cell cycle control.

1993 ◽  
Vol 13 (3) ◽  
pp. 1415-1423 ◽  
Author(s):  
E Yonish-Rouach ◽  
D Grunwald ◽  
S Wilder ◽  
A Kimchi ◽  
E May ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Interleukin 6 ◽  
Cell Cycle Progression ◽  
P53 Protein ◽  
Cell Cycle Control ◽  
Growth Arrest ◽  
Leukemic Cells ◽  
Temperature Sensitive ◽  
Permissive Temperature

M1 clone S6 myeloid leukemic cells do not express detectable p53 protein. When stably transfected with a temperature-sensitive mutant of p53, these cells undergo rapid cell death upon induction of wild-type (wt) p53 activity at the permissive temperature. This process has features of apoptosis. In a number of other cell systems, wt p53 activation has been shown to induce a growth arrest. Yet, wt 53 fails to induce a measurable growth arrest in M1 cells, and cell cycle progression proceeds while viability is being lost. There exists, however, a relationship between the cell cycle and p53-mediated death, and cells in G1 appear to be preferentially susceptible to the death-inducing activity of wt p53. In addition, p53-mediated M1 cell death can be inhibited by interleukin-6. The effect of the cytokine is specific to p53-mediated death, since apoptosis elicited by serum deprivation is refractory to interleukin-6. Our data imply that p53-mediated cell death is not dependent on the induction of a growth arrest but rather may result from mutually incompatible growth-regulatory signals.

p53-mediated cell death: relationship to cell cycle control

1993 ◽  
Vol 13 (3) ◽  
pp. 1415-1423
Author(s):  
E Yonish-Rouach ◽  
D Grunwald ◽  
S Wilder ◽  
A Kimchi ◽  
E May ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Interleukin 6 ◽  
Cell Cycle Progression ◽  
P53 Protein ◽  
Cell Cycle Control ◽  
Growth Arrest ◽  
Leukemic Cells ◽  
Temperature Sensitive ◽  
Permissive Temperature

M1 clone S6 myeloid leukemic cells do not express detectable p53 protein. When stably transfected with a temperature-sensitive mutant of p53, these cells undergo rapid cell death upon induction of wild-type (wt) p53 activity at the permissive temperature. This process has features of apoptosis. In a number of other cell systems, wt p53 activation has been shown to induce a growth arrest. Yet, wt 53 fails to induce a measurable growth arrest in M1 cells, and cell cycle progression proceeds while viability is being lost. There exists, however, a relationship between the cell cycle and p53-mediated death, and cells in G1 appear to be preferentially susceptible to the death-inducing activity of wt p53. In addition, p53-mediated M1 cell death can be inhibited by interleukin-6. The effect of the cytokine is specific to p53-mediated death, since apoptosis elicited by serum deprivation is refractory to interleukin-6. Our data imply that p53-mediated cell death is not dependent on the induction of a growth arrest but rather may result from mutually incompatible growth-regulatory signals.

scholarly journals Inhibition of p53-mediated growth arrest by overexpression of cyclin-dependent kinases.

1996 ◽  
Vol 16 (8) ◽  
pp. 4445-4455 ◽  
Author(s):  
K M Latham ◽  
S W Eastman ◽  
A Wong ◽  
P W Hinds
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Growth Arrest ◽  
Temperature Sensitive ◽  
Wild Type ◽  
Aberrant Expression ◽  
Cycle Progression ◽  
Cyclin Dependent Kinases ◽  
Rat Fibroblasts ◽  
Wild Type P53

Rat fibroblasts transformed by a temperature-sensitive mutant of murine p53 undergo a reversible growth arrest in G1 at 32.5 degrees C, the temperature at which p53 adopts a wild-type conformation. The arrested cells contain inactive cyclin-dependent kinase 2 (cdk2) despite the presence of high levels of cyclin E and cdk-activating kinase activity. This is due in part to p53-dependent expression of the p2l cdk inhibitor. Upon shift to 39 degrees C, wild-type p53 is lost and cdk2 activation and pRb phosphorylation occur concomitantly with loss of p2l. This p53-mediated growth arrest can be abrogated by overexpression of cdk4 and cdk6 but not cdk2 or cyclins, leading to continuous proliferation of transfected cells in the presence of wild-type p53 and p2l. Kinase-inactive counterparts of cdk4 and cdk6 also rescue these cells from growth arrest, implicating a noncatalytic role for cdk4 and cdk6 in this resistance to p53-mediated growth arrest. Aberrant expression of these cell cycle kinases may thus result in an oncogenic interference with inhibitors of cell cycle progression.

scholarly journals The Saccharomyces cerevisiae SDA1 gene is required for actin cytoskeleton organization and cell cycle progression

2000 ◽  
Vol 113 (7) ◽  
pp. 1199-1211
Author(s):  
G. Buscemi ◽  
F. Saracino ◽  
D. Masnada ◽  
M.L. Carbone
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cell Cycle ◽  
Dna Replication ◽  
Actin Cytoskeleton ◽  
Cell Cycle Progression ◽  
Temperature Sensitive ◽  
Permissive Temperature ◽  
Cycle Progression ◽  
Cytoskeleton Organization ◽  
Actin Cytoskeleton Organization

The organization of the actin cytoskeleton is essential for several cellular processes. Here we report the characterization of a Saccharomyces cerevisiae novel gene, SDA1, encoding a highly conserved protein, which is essential for cell viability and is localized in the nucleus. Depletion or inactivation of Sda1 cause cell cycle arrest in G(1) by blocking both budding and DNA replication, without loss of viability. Furthermore, sda1-1 temperature-sensitive mutant cells arrest at the non-permissive temperature mostly without detectable structures of polymerized actin, although a normal actin protein level is maintained, indicating that Sda1 is required for proper organization of the actin cytoskeleton. To our knowledge, this is the first mutation shown to cause such a phenotype. Recovery of Sda1 activity restores proper assembly of actin structures, as well as budding and DNA replication. Furthermore we show that direct actin perturbation, either in sda1-1 or in cdc28-13 cells released from G(1) block, prevents recovery of budding and DNA replication. We also show that the block in G(1) caused by loss of Sda1 function is independent of Swe1. Altogether our results suggest that disruption of F-actin structure can block cell cycle progression in G(1) and that Sda1 is involved in the control of the actin cytoskeleton.

scholarly journals P53 gene: major mutations in neoplasias and anticancer gene therapy

2012 ◽  
Vol 42 (5) ◽  
pp. 845-853 ◽  
Author(s):  
Caroline Rocha de Oliveira Lima ◽  
Rogério Elias Rabelo ◽  
Valcinir Aloísio Scalla Vulcani ◽  
Lorena Damasio Cardoso ◽  
Nicaelle Luan de Moura Sousa ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Gene Therapy ◽  
Molecular Weight ◽  
Cell Death ◽  
P53 Protein ◽  
Cell Cycle Control ◽  
P53 Gene ◽  
Neoplastic Transformation ◽  
Functional Aspects

The p53 gene encodes a protein that has molecular weight of 53kD and is also called p53 protein, being constantly studied for its classic concept of "genome guardian". This gene plays a range of essential functions to ensure the cell cycle control, in addition to playing a central role in carcinogenesis. With respect to neoplasias, it prevents the neoplastic transformation through three intricate mechanisms. Depending on the extent of the mutation, different responses may be sent by p53 and those range since the disruption of the cell cycle, the correction of the mutation through the activation of repair proteins or still, the induction of senescence or cell death by apoptosis. This review aims to address the structural and functional aspects of the p53 gene and protein, and also reaffirm their participation in the carcinogenesis control, approaching their major mutations and the anticancer gene therapy involving this gene.

scholarly journals The Interaction Between Ran and NTF2 is Required for Cell Cycle Progression

2000 ◽  
Vol 11 (8) ◽  
pp. 2617-2629 ◽  
Author(s):  
B. Booth Quimby ◽  
Cassandra A. Wilson ◽  
Anita H. Corbett
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Spindle Assembly Checkpoint ◽  
Cell Cycle Control ◽  
Spindle Assembly ◽  
Bound State ◽  
Small Gtpase ◽  
Temperature Sensitive ◽  
Dependent Manner

The small GTPase Ran is required for the trafficking of macromolecules into and out of the nucleus. Ran also has been implicated in cell cycle control, specifically in mitotic spindle assembly. In interphase cells, Ran is predominately nuclear and thought to be GTP bound, but it is also present in the cytoplasm, probably in the GDP-bound state. Nuclear transport factor 2 (NTF2) has been shown to import RanGDP into the nucleus. Here, we examine the in vivo role of NTF2 in Ran import and the effect that disruption of Ran imported into the nucleus has on the cell cycle. A temperature-sensitive (ts) mutant of Saccharomyces cerevisiae NTF2 that does not bind to Ran is unable to import Ran into the nucleus at the nonpermissive temperature. Moreover, when Ran is inefficiently imported into the nucleus, cells arrest in G2in aMAD2 checkpoint-dependent manner. These findings demonstrate that NTF2 is required to transport Ran into the nucleus in vivo. Furthermore, we present data that suggest that depletion of nuclear Ran triggers a spindle-assembly checkpoint-dependent cell cycle arrest.

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.

scholarly journals THAP5 is a human cardiac-specific inhibitor of cell cycle that is cleaved by the proapoptotic Omi/HtrA2 protease during cell death

2009 ◽  
Vol 297 (2) ◽  
pp. H643-H653 ◽  
Author(s):  
Meenakshi P. Balakrishnan ◽  
Lucia Cilenti ◽  
Zineb Mashak ◽  
Paiyal Popat ◽  
Emad S. Alnemri ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Human Heart ◽  
Cell Cycle Progression ◽  
Cell Cycle Control ◽  
Specific Inhibitor ◽  
Dual Function ◽  
Protein Levels ◽  
Cycle Arrest ◽  
Artery Disease

Omi/HtrA2 is a mitochondrial serine protease that has a dual function: while confined in the mitochondria, it promotes cell survival, but when released into the cytoplasm, it participates in caspase-dependent as well as caspase-independent cell death. To investigate the mechanism of Omi/HtrA2's function, we set out to isolate and characterize novel substrates for this protease. We have identified Thanatos-associated protein 5 (THAP5) as a specific interactor and substrate of Omi/HtrA2 in cells undergoing apoptosis. This protein is an uncharacterized member of the THAP family of proteins. THAP5 has a unique pattern of expression and is found predominantly in the human heart, although a very low expression is also seen in the human brain and muscle. THAP5 protein is localized in the nucleus and, when ectopically expressed, induces cell cycle arrest. During apoptosis, THAP5 protein is degraded, and this process can be blocked using a specific Omi/HtrA2 inhibitor, leading to reduced cell death. In patients with coronary artery disease, THAP5 protein levels substantially decrease in the myocardial infarction area, suggesting a potential role of this protein in human heart disease. This work identifies human THAP5 as a cardiac-specific nuclear protein that controls cell cycle progression. Furthermore, during apoptosis, THAP5 is cleaved and removed by the proapoptotic Omi/HtrA2 protease. Taken together, we provide evidence to support that THAP5 and its regulation by Omi/HtrA2 provide a new link between cell cycle control and apoptosis in cardiomyocytes.

scholarly journals Wild-type p53 gene expression induces granulocytic differentiation of HL-60 cells

Blood ◽  
1994 ◽  
Vol 83 (8) ◽  
pp. 2230-2237 ◽  
Author(s):  
S Soddu ◽  
G Blandino ◽  
G Citro ◽  
R Scardigli ◽  
G Piaggio ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cellular Response ◽  
P53 Protein ◽  
Cell Cycle Control ◽  
P53 Gene ◽  
Malignant Cell ◽  
Temperature Sensitive ◽  
Wild Type ◽  
Granulocytic Differentiation ◽  
Wild Type P53

Abstract Overexpression of wild-type p53 gene in malignant cell lines has been shown to inhibit cell proliferation in a number of cases. However, endogenous p53 protein seems to play little role in normal cell-cycle control as suggested by the normal development of p53 null mice, and by the low p53 protein levels expressed in most cell types. Recently, increased expression of endogenous p53 protein has been observed during the cellular response to DNA damage, as well as during differentiation of human hematopoietic cells. To study the role of the p53 gene in hematopoietic differentiation, we introduced the wild-type p53 gene or the temperature-sensitive p53(Val135) mutant into p53-deficient HL-60 promyelocytic leukemia cells. Morphological analysis, flow-cytometric determination of granulocytic or monocytic surface markers, and ability to reduce nitroblue tetrazolium (NBT) demonstrated that expression of exogenous wild-type p53 gene in HL-60 cells induces differentiation through the granulocytic pathway. Proliferation and cell-cycle analysis performed early after expression of wild-type p53 showed that induction of differentiation is not coupled with growth arrest, which suggests that p53 is involved in differentiation independently of its activity on the cell cycle.

IL6 Protection of Myeloid Leukemic Cells Against P53 Induced Apoptosis Is Mediated by Activation of P13kinase/AKT and Stabilization of C-FLIP.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1271-1271
Author(s):  
Diana L. Vesely ◽  
Barbara Hoffman ◽  
Dan A. Liebermann
Keyword(s):  
Cell Lines ◽  
P53 Protein ◽  
Leukemic Cells ◽  
Temperature Sensitive ◽  
Permissive Temperature ◽  
Akt Inhibitor ◽  
Critical Determinant ◽  
Survival Pathway ◽  
Ligand Expression ◽  
Induced Apoptosis

Abstract Myeloid leukemic cells (M1) proliferate continuously in culture unless induced by Interleukin-6 (IL6) to undergo a terminal differentiation program into macrophages, followed by apoptosis. M1 cells lack the tumor suppressor p53, which is a critical determinant of the cellular decision to either growth arrest and repair DNA damage or to undergo apoptosis. Activation of a temperature sensitive p53 protein (p53 val) at the permissive temperature in M1 cells results in rapid apoptosis. IL6 treatment blocks this p53-mediated apoptosis. Towards understanding the basis for this p53-mediated apoptosis and its abrogation by IL6, we have shown that at the permissive temperature p53 activates the pro-apoptotic Fas/CD95 pathway by up regulating the Fas/CD95 receptor and cleaving antiapoptotic c-FLIP. On the other hand, antagonistic Fas antibody protects against apoptosis. IL6 decreases Fas/CD95 ligand expression and prevents cleavage of FLIP. Treatment of M1p53ts cells with the specific Akt inhibitor Ly294002 abrogated IL6 protection and resulted in Flip cleavage, suggesting that IL-6 blocks apoptosis by phosphorylating and activating P13kinase/Akt, which in turn promotes FLIP stability. Inhibition of the ERK pro-survival pathway did not abrogate IL6 protection against p53 apoptosis like Akt inhibition caused. Nevertheless M1p53ts-Flip cell lines fail to completely protect against p53 mediated apoptosis, suggesting that FLIP is itself insufficient to protect against apoptosis. Therefore we examined what other proteins may synergize with FLIP to protect from apoptosis, and found that that the pro-survival bcl2 protein family member MCL-1 is strongly up regulated by IL6 in our M1p53 cell line. Generation of M1p53-FLIP-MCL1, M1p53-MCL1, and M1p53 -uncleavable FLIP cell lines is underway to determine whether there is synergy between MCL-1 and FLIP in escape from p53 mediated apoptosis of M1p53 cells. Thus far taken together these data support a model for leukemic progression where cells that acquire the ability to produce an autocrine survival factor, such as IL6, can bypass normal p53 surveillance function by targeting downstream inhibitors of apoptosis such Akt, c-Flip and MCL-1.

scholarly journals Expression of the p53 tumor suppressor gene induces differentiation and promotes induction of differentiation by 1,25-dihydroxycholecalciferol in leukemic U-937 cells

Blood ◽  
1996 ◽  
Vol 87 (3) ◽  
pp. 1064-1074 ◽  
Author(s):  
M Ehinger ◽  
G Bergh ◽  
T Olofsson ◽  
B Baldetorp ◽  
I Olsson ◽  
...  
Keyword(s):  
Cell Death ◽  
Flow Cytometric Analysis ◽  
Negative Control ◽  
Leukemic Cells ◽  
Temperature Sensitive ◽  
Permissive Temperature ◽  
Wild Type ◽  
Fourfold Increase ◽  
Induction Of Differentiation ◽  
Wild Type P53

Leukemic U-937 cells, which lack normal p53, were stably transfected with a temperature-sensitive mutant of p53 to investigate the consequences for growth and differentiation. On induction of wild-type p53 activity at the permissive temperature, some of these cells underwent maturation as judged by the capacity for oxidative burst and the appearance of monocyte related cell surface molecules. Moreover, wild-type p53-expressing cells were more sensitive than p53-negative control cells to induction of differentiation by 1,25- dihydroxycholecalciferol; a twofold to fourfold increase of the fraction of cells showing signs of terminal maturation was observed when wild-type p53-expressing cells were incubated with 1,25- dihydroxycholecalciferol at concentrations that only slightly affected control cells. Whereas wild-type p53 activity per se induced maturation of certain cells, other underwent cell death judging from the reduced capability to exclude trypan blue and the appearance of fragmented DNA in flow cytometric analysis. The p53-induced cell death could be inhibited by incubation with 1,25-dihydroxy-cholecalciferol, but not all-trans retinoic acid. Thus, 1,25-dihydroxycholecalciferol, seemed to increase the survival of wild-type p53-expressing cells and to cooperate with wild-type p53 to induce differentiation. The data imply that p53-mediated maturation in U-937 cells depends on optimal regulation of signals for differentiation, survival and proliferation, and suggest a role for p53 in the differentiation induction of leukemic cells.

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