scholarly journals Targeting the p53 Pathway in Ewing Sarcoma

Sarcoma ◽  
2011 ◽  
Vol 2011 ◽  
pp. 1-17 ◽  
Author(s):  
Paul M. Neilsen ◽  
Kathleen I. Pishas ◽  
David F. Callen ◽  
David M. Thomas
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Ewing Sarcoma ◽  
Gene Rearrangement ◽  
Cell Cycle Checkpoints ◽  
Wild Type ◽  
Damage Cell ◽  
Downstream Signaling ◽  
Functional Capabilities ◽  
Wild Type P53

The p53 tumour suppressor plays a pivotal role in the prevention of oncogenic transformation. Cancers frequently evade the potent antitumour surveillance mechanisms of p53 through mutation of theTP53gene, with approximately 50% of all human malignancies expressing dysfunctional, mutated p53 proteins. Interestingly, genetic lesions in theTP53gene are only observed in 10% of Ewing Sarcomas, with the majority of these sarcomas expressing a functional wild-type p53. In addition, the p53 downstream signaling pathways and DNA-damage cell cycle checkpoints remain functionally intact in these sarcomas. This paper summarizes recent insights into the functional capabilities and regulation of p53 in Ewing Sarcoma, with a particular focus on the cross-talk between p53 and the EWS-FLI1 gene rearrangement frequently associated with this disease. The development of several activators of p53 is discussed, with recent evidence demonstrating the potential of small molecule p53 activators as a promising systemic therapeutic approach for the treatment of Ewing Sarcomas with wild-type p53.

scholarly journals New Insights into p53 Signaling and Cancer Cell Response to DNA Damage: Implications for Cancer Therapy

2012 ◽  
Vol 2012 ◽  
pp. 1-16 ◽  
Author(s):  
Razmik Mirzayans ◽  
Bonnie Andrais ◽  
April Scott ◽  
David Murray
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Apoptotic Cell ◽  
Cell Types ◽  
Cell Cycle Checkpoint ◽  
Cell Cycle Checkpoints ◽  
Cancer Therapies ◽  
Wild Type ◽  
P53 Signaling ◽  
Upstream Kinase

Activation of the p53 signaling pathway by DNA-damaging agents was originally proposed to result either in cell cycle checkpoint activation to promote survival or in apoptotic cell death. This model provided the impetus for numerous studies focusing on the development of p53-based cancer therapies. According to recent evidence, however, most p53 wild-type human cell types respond to ionizing radiation by undergoing stress-induced premature senescence (SIPS) and not apoptosis. SIPS is a sustained growth-arrested state in which cells remain viable and secrete factors that may promote cancer growth and progression. Thep21WAF1(hereafter p21) protein has emerged as a key player in the p53 pathway. In addition to its well-studied role in cell cycle checkpoints, p21 regulates p53 and its upstream kinase (ATM), controls gene expression, suppresses apoptosis, and induces SIPS. Herein, we review these and related findings with human solid tumor-derived cell lines, report new data demonstrating dynamic behaviors of p53 and p21 in the DNA damage response, and examine the gain-of-function properties of cancer-associated p53 mutations. We point out obstacles in cancer-therapeutic strategies that are aimed at reactivating the wild-type p53 function and highlight some alternative approaches that target the apoptotic threshold in cancer cells with differing p53 status.

scholarly journals Specific Role of Chk1 Phosphorylations in Cell Survival and Checkpoint Activation

2007 ◽  
Vol 27 (7) ◽  
pp. 2572-2581 ◽  
Author(s):  
Hiroyuki Niida ◽  
Yuko Katsuno ◽  
Birendranath Banerjee ◽  
M. Prakash Hande ◽  
Makoto Nakanishi
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Protein Kinase ◽  
Cell Survival ◽  
Cell Cycle Checkpoints ◽  
Mitotic Catastrophe ◽  
Wild Type ◽  
Checkpoint Activation ◽  
Multifunctional Protein

ABSTRACT Chk1 is a multifunctional protein kinase that plays essential roles in cell survival and cell cycle checkpoints. Chk1 is phosphorylated at multiple sites by several protein kinases, but the precise effects of these phosphorylations are largely unknown. Using a knockout-knockin system, we examined the abilities of Chk1 mutants to reverse the defects of Chk1-null cells. Wild-type Chk1 could rescue all the defects of Chk1-null cells. Like endogenous Chk1, wild-type Chk1 localized in both the cytoplasm and the nucleus, and its centrosomal association was enhanced by DNA damage. The mutation at S345 resulted in mitotic catastrophe, impaired checkpoints, and loss of the ability to localize in the cytoplasm, but the mutant retained the ability to be released from chromatin upon encountering genotoxic stressors. In contrast, the mutation at S317 resulted in impaired checkpoints and loss of chromatin release upon encountering genotoxic stressors, but its mutant retained the abilities to prevent mitotic catastrophes and to localize in the cytoplasm, suggesting the distinct effects of these phosphorylations. The forced immobilization of S317A/S345A in centrosomes resulted in the prevention of apoptosis in the presence or absence of DNA damage. Thus, two-step phosphorylation of Chk1 at S317 and S345 appeared to be required for proper localization of Chk1 to centrosomes.

scholarly journals The transcription factors TFE3 and TFEB amplify p53 dependent transcriptional programs in response to DNA damage

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Eutteum Jeong ◽  
Owen A Brady ◽  
José A Martina ◽  
Mehdi Pirooznia ◽  
Ilker Tunc ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Transcription Factors ◽  
P53 Protein ◽  
Cell Cycle Control ◽  
Cell Cycle Checkpoints ◽  
Dependent Manner ◽  
Double Knockout ◽  
Protein Levels ◽  
Regulation Of Cell Cycle

The transcription factors TFE3 and TFEB cooperate to regulate autophagy induction and lysosome biogenesis in response to starvation. Here we demonstrate that DNA damage activates TFE3 and TFEB in a p53 and mTORC1 dependent manner. RNA-Seq analysis of TFEB/TFE3 double-knockout cells exposed to etoposide reveals a profound dysregulation of the DNA damage response, including upstream regulators and downstream p53 targets. TFE3 and TFEB contribute to sustain p53-dependent response by stabilizing p53 protein levels. In TFEB/TFE3 DKOs, p53 half-life is significantly decreased due to elevated Mdm2 levels. Transcriptional profiles of genes involved in lysosome membrane permeabilization and cell death pathways are dysregulated in TFEB/TFE3-depleted cells. Consequently, prolonged DNA damage results in impaired LMP and apoptosis induction. Finally, expression of multiple genes implicated in cell cycle control is altered in TFEB/TFE3 DKOs, revealing a previously unrecognized role of TFEB and TFE3 in the regulation of cell cycle checkpoints in response to stress.

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.

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