scholarly journals Impaired p53 Expression, Function, and Nuclear Localization in Calreticulin-deficient Cells

2004 ◽  
Vol 15 (4) ◽  
pp. 1862-1870 ◽  
Author(s):  
Nasrin Mesaeli ◽  
Clark Phillipson
Keyword(s):  
Dna Damage ◽  
Binding Site ◽  
Nuclear Localization ◽  
P53 Protein ◽  
Nuclear Accumulation ◽  
P53 Expression ◽  
Cycle Arrest ◽  
Expression Of Genes ◽  
The Stability

The tumor suppressor protein, p53 is a transcription factor that not only activates expression of genes containing the p53 binding site but also can repress the expression of some genes lacking this binding site. Previous studies have shown that overexpression of wild-type p53 leads to apoptosis and cell cycle arrest. DNA damage, such as that caused by UV irradiation, results in p53 stabilization and nuclear localization that subsequently induces apoptosis. Recently, the level of calreticulin (CRT) has been correlated with the rate of apoptosis. Therefore, the aim of this study was to investigate the role of CRT in the regulation of apoptosis via modulating p53 function and expression. Here we show a significant decrease in both basal and DNA damage induced p53 functions in the CRT-deficient cells (crt-/-). This study is the first to demonstrate that CRT function is required for the stability and localization of the p53 protein. By using immuonocytochemical techniques, we showed that observed changes in p53 in the crt-/- cells are due to the nuclear accumulation of Mdm2 (murine double minute gene). These results, lead us to conclude that CRT regulates p53 function by affecting its rate of degradation and nuclear localization.

DNA damage triggers the nuclear accumulation of RASSF6 tumor suppressor protein via CDK9 and BAF53 to regulate p53-target gene transcription

2021 ◽  
Author(s):  
Joshua Agbemefa Kuleape ◽  
Shakhawoat Hossain ◽  
Caleb Kwame Sinclear ◽  
Takanobu Shimizu ◽  
Hiroaki Iwasa ◽  
...  
Keyword(s):  
Dna Damage ◽  
Tumor Suppressor ◽  
Gene Transcription ◽  
Nuclear Export ◽  
Target Gene ◽  
Nuclear Accumulation ◽  
P53 Expression ◽  
Cycle Arrest ◽  
P53 Target Gene ◽  
Target Gene Transcription

RASSF6, a member of the tumor suppressor Ras-association domain family (RASSF) proteins, regulates cell cycle arrest and apoptosis via p53 and plays a tumor suppressor role. We previously reported that RASSF6 blocks MDM2-mediated p53 degradation and enhances p53 expression. In this study, we demonstrated that RASSF6 has nuclear-localization and nuclear-export signals and that DNA damage triggers the nuclear accumulation of RASSF6. We found that RASSF6 directly binds to BAF53, the component of SWI/SNF complex. DNA damage induces CDK9-mediated phosphorylation of BAF53, which enhances the interaction with RASSF6 and increases the amount of RASSF6 in the nucleus. Subsequently, RASSF6 augments the interaction between BAF53 and BAF60a, another component of SWI/SNF complex, and further promotes the interaction of BAF53 and BAF60a with p53. BAF53 silencing or BAF60a silencing attenuates RASSF6-mediated p53-target gene transcription and apoptosis. Thus, RASSF6 is involved in the regulation of DNA damage-induced complex formation including CDK9, BAF53, BAF60a, and p53.

scholarly journals Mutated p53 in HGSC—From a Common Mutation to a Target for Therapy

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3465
Author(s):  
Aya Saleh ◽  
Ruth Perets
Keyword(s):  
Cancer Progression ◽  
Target Genes ◽  
P53 Protein ◽  
Genetic Alterations ◽  
Common Mutation ◽  
Missense Mutations ◽  
P53 Expression ◽  
Histologic Subtype ◽  
Tp53 Mutations

Mutations in tumor suppressor gene TP53, encoding for the p53 protein, are the most ubiquitous genetic variation in human ovarian HGSC, the most prevalent and lethal histologic subtype of epithelial ovarian cancer (EOC). The majority of TP53 mutations are missense mutations, leading to loss of tumor suppressive function of p53 and gain of new oncogenic functions. This review presents the clinical relevance of TP53 mutations in HGSC, elaborating on several recently identified upstream regulators of mutant p53 that control its expression and downstream target genes that mediate its roles in the disease. TP53 mutations are the earliest genetic alterations during HGSC pathogenesis, and we summarize current information related to p53 function in the pathogenesis of HGSC. The role of p53 is cell autonomous, and in the interaction between cancer cells and its microenvironment. We discuss the reduction in p53 expression levels in tumor associated fibroblasts that promotes cancer progression, and the role of mutated p53 in the interaction between the tumor and its microenvironment. Lastly, we discuss the potential of TP53 mutations to serve as diagnostic biomarkers and detail some more advanced efforts to use mutated p53 as a therapeutic target in HGSC.

Role of P53 Mutations in the Radiosensitivity Status of Tumor Cells

1998 ◽  
Vol 84 (5) ◽  
pp. 517-520 ◽  
Author(s):  
Vincenzo Chiarugi ◽  
Lucia Magnelli ◽  
Marina Cinelli
Keyword(s):  
Dna Damage ◽  
Cellular Response ◽  
P53 Protein ◽  
Cell Cycle Control ◽  
P53 Mutations ◽  
Wild Type ◽  
Bladder Tumors ◽  
Variable Effect ◽  
Wild Type P53

Wild-type p53 is involved in cellular response to DNA damage including cell cycle control, DNA repair and activation of apoptosis. Accumulation of p53 protein following DNA damage may initiate the apoptotic process, resulting in cell death. DNA damage induced by radiation is an example of apoptotic stimulus involving p53. Regulation of apoptosis by p53 can occur through transcriptional regulation of pro-apoptotic (e.g. bax) and anti-apoptotic (e.g. bel-2) factors. Although wild-type p53 usually sensitizes cells to radiation therapy, p53 mutations have a variable effect on radiation response. For example p53 mutations in bone or breast tumors have been found to be associated with resistance to chemotherapeutic drugs or ionizing radiation. Mutated p53 has has been reported to increase sensitivity to radiation and drugs in colorectal and bladder tumors. The present brief commentary tries to find an explanation at molecular level of these conflicting results.

scholarly journals Cluster Analysis of p53 Binding Site Sequences Reveals Subsets with Different Functions

2016 ◽  
Vol 15 ◽  
pp. CIN.S39968
Author(s):  
Ji-Hyun Lim ◽  
Natasha S. Latysheva ◽  
Richard D. Iggo ◽  
Daniel Barker
Keyword(s):  
Binding Site ◽  
Binding Sites ◽  
P53 Protein ◽  
Species Conservation ◽  
Structural Data ◽  
Functional Differentiation ◽  
Dna Binding Domain ◽  
Response Elements ◽  
Cycle Arrest ◽  
Important Regulator

p53 is an important regulator of cell cycle arrest, senescence, apoptosis and metabolism, and is frequently mutated in tumors. It functions as a tetramer, where each component dimer binds to a decameric DNA region known as a response element. We identify p53 binding site subtypes and examine the functional and evolutionary properties of these subtypes. We start with over 1700 known binding sites and, with no prior labeling, identify two sets of response elements by unsupervised clustering. When combined, they give rise to three types of p53 binding sites. We find that probabilistic and alignment-based assessments of cross-species conservation show no strong evidence of differential conservation between types of binding sites. In contrast, functional analysis of the genes most proximal to the binding sites provides strong bioinformatic evidence of functional differentiation between the three types of binding sites. Our results are consistent with recent structural data identifying two conformations of the L1 loop in the DNA binding domain, suggesting that they reflect biologically meaningful groups imposed by the p53 protein structure.

scholarly journals An ATP/ADP-Dependent Molecular Switch Regulates the Stability of p53-DNA Complexes

1999 ◽  
Vol 19 (11) ◽  
pp. 7501-7510 ◽  
Author(s):  
Andrei L. Okorokov ◽  
Jo Milner
Keyword(s):  
Dna Damage ◽  
Dna Binding ◽  
Cellular Response ◽  
Atp Hydrolysis ◽  
P53 Protein ◽  
Molecular Switch ◽  
Dna Complexes ◽  
Switch Mechanism ◽  
The Stability ◽  
First Time

ABSTRACT Interaction with DNA is essential for the tumor suppressor functions of p53. We now show, for the first time, that the interaction of p53 with DNA can be stabilized by small molecules, such as ADP and dADP. Our results also indicate an ATP/ADP molecular switch mechanism which determines the off-on states for p53-DNA binding. This ATP/ADP molecular switch requires dimer-dimer interaction of the p53 tetramer. Dissociation of p53-DNA complexes by ATP is independent of ATP hydrolysis. Low-level ATPase activity is nonetheless associated with ATP-p53 interaction and may serve to regenerate ADP-p53, thus recycling the high-affinity DNA binding form of p53. The ATP/ADP regulatory mechanism applies to two distinct types of p53 interaction with DNA, namely, sequence-specific DNA binding (via the core domain of the p53 protein) and binding to sites of DNA damage (via the C-terminal domain). Further studies indicate that ADP not only stabilizes p53-DNA complexes but also renders the complexes susceptible to dissociation by specific p53 binding proteins. We propose a model in which the DNA binding functions of p53 are regulated by an ATP/ADP molecular switch, and we suggest that this mechanism may function during the cellular response to DNA damage.

scholarly journals Identification of the myogenetic oligodeoxynucleotides (myoDNs) that promote differentiation of skeletal muscle myoblasts by targeting nucleolin

2020 ◽  
Author(s):  
Sayaka Shinji ◽  
Koji Umezawa ◽  
Yuma Nihashi ◽  
Shunichi Nakamura ◽  
Takeshi Shimosato ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Skeletal Muscle ◽  
Myogenic Differentiation ◽  
P53 Protein ◽  
Lactobacillus Rhamnosus ◽  
Conformational State ◽  
Myotube Formation ◽  
Cycle Arrest ◽  
Expression Of Genes ◽  
Myogenic Precursor

AbstractHerein we report that the 18-base telomeric oligodeoxynucleotides (ODNs) designed from the Lactobacillus rhamnosus GG genome promote differentiation of skeletal muscle myoblasts which are myogenic precursor cells. We termed these myogenetic ODNs (myoDNs). The activity of one of the myoDNs, iSN04, was independent of Toll-like receptors, but dependent on its conformational state. Molecular simulation and iSN04 mutants revealed stacking of the 13-15th guanines as a core structure for iSN04. The alkaloid berberine bound to the guanine stack and enhanced iSN04 activity, probably by stabilizing and optimizing iSN04 conformation. We further identified nucleolin as an iSN04-binding protein. Results showed that iSN04 antagonizes nucleolin, increases the levels of p53 protein translationally suppressed by nucleolin, and eventually induces myotube formation by modulating the expression of genes involved in myogenic differentiation and cell cycle arrest. This study shows that bacterial-derived myoDNs serve as aptamers and are potential nucleic acid drugs directly targeting myoblasts.

scholarly journals Role of P53 protein in activation of atm- and parp-mediated dna damage repair (DDR) pathways induced by topoisomerase type II inhibitors

2016 ◽  
Vol 97 (2) ◽  
pp. 245-249
Author(s):  
B.R. Ramazanov ◽  
◽  
R.R. Khusnutdinov ◽  
A.R. Galembikova ◽  
P.D. Dunaev ◽  
...  
Keyword(s):  
Dna Damage ◽  
P53 Protein ◽  
Dna Damage Repair ◽  
Type Ii ◽  
Damage Repair

scholarly journals p38 Mitogen-Activated Protein Kinase- and HuR-Dependent Stabilization of p21Cip1 mRNA Mediates the G1/S Checkpoint

2009 ◽  
Vol 29 (16) ◽  
pp. 4341-4351 ◽  
Author(s):  
Vanesa Lafarga ◽  
Ana Cuadrado ◽  
Isabel Lopez de Silanes ◽  
Rocio Bengoechea ◽  
Oscar Fernandez-Capetillo ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Protein Kinase ◽  
Cell Cycle Arrest ◽  
P38 Mapk ◽  
Mitogen Activated Protein Kinase ◽  
Γ Radiation ◽  
Cycle Arrest ◽  
Mitogen Activated Protein

ABSTRACT Activation of p38 mitogen-activated protein kinase (MAPK) plays an important role in the G2/M cell cycle arrest induced by DNA damage, but little is known about the role of this signaling pathway in the G1/S transition. Upregulation of the cyclin-dependent kinase inhibitor p21Cip1 is thought to make a major contribution to the G1/S cell cycle arrest induced by γ radiation. We show here that inhibition of p38 MAPK impairs p21Cip1 accumulation and, as a result, the ability of cells to arrest in G1 in response to γ radiation. We found that p38 MAPK induces p21Cip1 mRNA stabilization, without affecting its transcription or the stability of the protein. In particular, p38 MAPK phosphorylates the mRNA binding protein HuR on Thr118, which results in cytoplasmic accumulation of HuR and its enhanced binding to the p21Cip1 mRNA. Our findings help to understand the emerging role of p38 MAPK in the cellular responses to DNA damage and reveal the existence of p53-independent networks that cooperate in modulating p21Cip1 levels at the G1/S checkpoint.

Sign in / Sign up

Export Citation Format

Share Document