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Functional interplay between p53 and p53/p73 isoforms in human melanoma

Unlike other tumors, TP53 is rarely mutated in melanoma ; however, it fails to function as a tumor suppressor. We assume that its functions might be altered through interactions with several family members. To elucidate the potential interplay among family members, we analysed the expression profiles of p53/p73 isoforms in a panel of melanoma cell lines, metastatic melanoma specimens and healthy corresponding tissue. Using qPCR, lower levels of Δ40p53 and ΔNp73 were observed in tumor samples compared to healthy tissue. Protein expression of Δ133p53α, Δ160p53α and ΔNp73α isoforms was elevated in tumor tissue, whereas ∆Np73β was downregulated. The results in melanoma cell lines, in general, support these findings. In addition, we correlated expression profiles with clinical features and outcome. Higher Δ133p53β and p53α mRNA expression had a negative impact on the overall survival. Shorter overall survival was also connected with lower p53β gene expression levels. Furthermore, we examined the interactions between p53 and p53/p73 isoforms as well as their effect on p53 transactivation capacity in wild-type p53 melanoma cell lines. As expected, we have found interactions between p53α and small molecular weight p53 isoforms (p53β, p53γ, Δ40p53α, Δ40p53β and Δ133p53α) as well as with both ΔNp73α and ΔNp73β in melanoma cell lines. These results suggest that p53 and p73 isoforms may contribute to inactivation of p53 protein function in melanoma cells by forming the direct protein interactions. Consequently, reporter and apoptosis assay confirmed that p53 and p73 isoforms interfere with p53α activity thus regulating the expression of genes involved in cell cycle, apoptosis and senescence. In conclusion, all examined genes may have implications in melanoma development and functional inactivity of TP53. Targeting two independent pathways could be a promising strategy in melanoma treatment.

melanoma ; p53 ; p73 ; NME ; GLI

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