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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Aberrant regulation and function of wild-type p53 in radioresistant melanoma cells
K Satyamoorthy1, N H Chehab, M J Waterman
1The Wistar Institute, Philadelphia, Pennsylvania 19104-4268, USA.
Abstract:
Sporadic human tumors and the hereditary cancer predisposition syndrome Li-Fraumeni are frequently associated with mutations in the p53 tumor suppressor gene that compromise its ability to function as a DNA damage checkpoint. A subset of Li-Fraumeni patients with wild-type p53 alleles have mutations in chk2/hcds1, one of the genes signaling the presence of DNA damage to the p53 protein. This suggests that p53 may be kept inactive in human cancer by mutations targeting DNA damage signaling pathways. Melanoma cells are highly radioresistant, yet they express wild-type p53 protein, raising the possibility of defects in the pathways that activate p53 in response to DNA damage. We have described a chk2/hcds1-independent DNA damage signaling pathway that targets Ser-376 within the COOH terminus of p53 for dephosphorylation and leads to increased p53 functional activity. We now report that in several human melanoma cell lines that express wild-type p53, the phosphorylation state of Ser-376 was not regulated by DNA damage. In these cell lines, neither the endogenous wild-type p53 protein nor high levels of ectopic wild-type p53 led to cell cycle arrest or apoptosis. Thus, defective activation of p53 in response to DNA damage may underlie the radioresistance of human melanoma cells.
Insights
Mutations in DNA damage signaling pathways can inactivate the p53 tumor suppressor. In melanoma, defective p53 activation, not p53 mutations, may cause radioresistance.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Mutations in the p53 tumor suppressor gene are common in sporadic human tumors and Li-Fraumeni syndrome, impairing DNA damage response.
- While some Li-Fraumeni patients have wild-type p53, they may harbor mutations in DNA damage signaling genes like chk2/hcds1.
- This suggests that inactivation of p53 in cancer can occur through defects in upstream DNA damage signaling pathways.
Purpose of the Study:
- To investigate the mechanism of radioresistance in human melanoma cells, which typically express wild-type p53.
- To determine if defects in p53 activation pathways contribute to melanoma's resistance to DNA damage.
- To examine the role of the Ser-376 phosphorylation site in p53 activation in melanoma.
Main Methods:
- Analysis of wild-type p53 phosphorylation status at Ser-376 in response to DNA damage in human melanoma cell lines.
- Assessment of cell cycle arrest and apoptosis induction following DNA damage in melanoma cells expressing wild-type p53.
- Evaluation of both endogenous and ectopically expressed wild-type p53 function.
Main Results:
- Several human melanoma cell lines with wild-type p53 showed no regulated phosphorylation of Ser-376 upon DNA damage.
- Neither endogenous nor overexpressed wild-type p53 induced cell cycle arrest or apoptosis in these melanoma cells after DNA damage.
- These findings indicate a failure in the DNA damage-induced activation of p53 in radioresistant melanoma cells.
Conclusions:
- Defective activation of the p53 pathway, specifically the inability to regulate Ser-376 phosphorylation in response to DNA damage, may explain the radioresistance of human melanoma.
- This highlights the importance of intact DNA damage signaling pathways for p53 function in preventing cancer progression and treatment resistance.
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