Abstract
TAp73, a member of the p53 tumor suppressor family, can substitute for p53 function, especially in p53-null and p53-mutant cells. However, TAp73 enrichment and phosphorylation change its transcriptional activity. Previously, we found that the antitumor function of TAp73 was reactivated by dephosphorylation. Polo-like kinase 2 (PLK2) plays an important role in bone development. Using a biological information database and phosphorylation prediction software, we hypothesized that PLK2 phosphorylates TAp73 and inhibits TAp73 function in osteosarcomas. Actually,we determined that PLK2 physically binds to and phosphorylates TAp73 when TAp73 protein abundance is up-regulated by cisplatin. PLK2-phosphorylated TAp73 at residue Ser48 within the TA domain; phosphorylation of TAp73 was abolished by mutating this residue. Moreover, PLK2 inhibition combined with cisplatin treatment in osteosarcoma Saos2 cells up-regulated p21 and puma mRNA expression to a greater extent than cisplatin treatment alone. Inhibiting PLK2 in TAp73-enriched Saos2 cells resulted in inhibited cell proliferation, increased apoptosis, G1 phase arrest, and decreased cell invasion. However, these changes did not occur in TAp73 knockdown Saos2 cells. In conclusion, these findings reveal a novel PLK2 function in the phosphorylation of TAp73, which prevents TAp73 activity in osteosarcoma cells. Thereby, this research provides an insight into the clinical treatment of malignant tumors overexpressing TAp73.
Highlights
Osteosarcoma is the most common bone malignancy
Negative co-IP results were observed between Polo-like kinase 2 (PLK2) and TAp73, as the abundance of TAp73 was low in Saos2 cells under normal culture conditions
Because PLK2 is a kinase, we investigated whether it phosphorylates TAp73
Summary
Osteosarcoma is the most common bone malignancy. It predominantly affects adolescents and young adults [1], and its treatment remains challenging [2].The tumor suppressor protein p53 plays a very important role in tumor suppression. Osteosarcoma is the most common bone malignancy. It predominantly affects adolescents and young adults [1], and its treatment remains challenging [2]. The tumor suppressor protein p53 plays a very important role in tumor suppression. In more than half of human cancers, this protein is mutated or deleted through different mechanisms [3, 4]. The TAp73 protein is a member of the p53 family. It has a similar structure to p53 and activates some p53 target genes [5]. TAp73 plays varying roles under different conditions that have yet to be completely elucidated. In contrast with p53, TAp73 is rarely mutated and is frequently overexpressed in human
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