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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Altered Expression of Shorter p53 Family Isoforms Can Impact Melanoma Aggressiveness
Ana Tadijan1, Francesca Precazzini2,3, Nikolina Hanžić1
1Laboratory for Protein Dynamics, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia.
Abstract:
Cutaneous melanoma is the most aggressive form of skin cancer. Despite the significant advances in the management of melanoma in recent decades, it still represents a challenge for clinicians. The TP53 gene, the guardian of the genome, which is altered in more than 50% of human cancers, is rarely mutated in melanoma. More recently, researchers started to appreciate the importance of shorter p53 isoforms as potential modifiers of the p53-dependent responses. We analyzed the expression of p53 and p73 isoforms both at the RNA and protein level in a panel of melanoma-derived cell lines with different TP53 and BRAF status, in normal conditions or upon treatment with common anti-cancer DNA damaging agents or targeted therapy. Using lentiviral vectors, we also generated stable clones of H1299 p53 null cells over-expressing the less characterized isoforms Δ160p53α, Δ160p53β, and Δ160p53γ. Further, we obtained two melanoma-derived cell lines resistant to BRAF inhibitor vemurafenib. We observed that melanoma cell lines expressed a wide array of p53 and p73 isoforms, with Δ160p53α as the most variable one. We demonstrated for the first time that Δ160p53α, and to a lesser extent Δ160p53β, can be recruited on chromatin, and that Δ160p53γ can localize in perinuclear foci; moreover, all Δ160p53 isoforms can stimulate proliferation and in vitro migration. Lastly, vemurafenib-resistant melanoma cells showed an altered expression of p53 and p73 isoforms, namely an increased expression of potentially pro-oncogenic Δ40p53β and a decrease in tumor-suppressive TAp73β. We therefore propose that p53 family isoforms can play a role in melanoma cells' aggressiveness.
Insights
Shorter p53 and p73 isoforms, particularly Δ160p53, influence melanoma cell aggressiveness and proliferation. Altered expression of these p53 isoforms is linked to vemurafenib resistance in melanoma.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Cutaneous melanoma is an aggressive skin cancer, posing clinical challenges despite advances.
- The tumor suppressor TP53 gene is rarely mutated in melanoma, suggesting alternative mechanisms of p53 pathway dysregulation.
- Emerging research highlights the role of shorter p53 isoforms in modulating p53-dependent cellular responses.
Purpose of the Study:
- To investigate the expression and function of p53 and p73 isoforms in melanoma.
- To determine the impact of specific p53 isoforms (Δ160p53α, β, γ) on melanoma cell behavior.
- To analyze isoform expression changes in vemurafenib-resistant melanoma cells.
Main Methods:
- Analysis of p53 and p73 isoform expression (RNA and protein) in melanoma cell lines.
- Generation of stable cell lines overexpressing Δ160p53 isoforms using lentiviral vectors.
- Assessment of isoform localization, chromatin recruitment, and effects on proliferation and migration.
- Characterization of isoform expression in vemurafenib-resistant melanoma cells.
Main Results:
- Melanoma cells express diverse p53 and p73 isoforms, with variable Δ160p53α expression.
- Δ160p53α and Δ160p53β isoforms are recruited to chromatin; Δ160p53γ localizes in perinuclear foci.
- All Δ160p53 isoforms promote melanoma cell proliferation and in vitro migration.
- Vemurafenib-resistant cells exhibit altered p53/p73 isoform expression, including increased Δ40p53β and decreased TAp73β.
Conclusions:
- p53 and p73 isoforms are expressed in melanoma and can influence cellular aggressiveness.
- Δ160p53 isoforms possess oncogenic potential by promoting proliferation and migration.
- Altered p53/p73 isoform profiles may contribute to melanoma treatment resistance.
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