p53 and Its Isoforms in Renal Cell Carcinoma—Do They Matter?

Abstract

p53 is a transcription al factor responsible for the maintenance of cellular homeostasis. It has been shown that more than 50% of tumors are connected with mutations in the Tp53 gene. These mutations cause a disturbance in cellular response to stress, and eventually, cancer development. Apart from the full-length p53, at least twelve isoforms of p53 have been characterized. They are able to modulate p53 activity under stress conditions. In 2020, almost a half of million people around the world were diagnosed with renal cancer. One genetic disturbance which is linked to the most common type of kidney cancer, renal cell carcinoma, RCC, occurs from mutations in the VHL gene. Recent data has revealed that the VHL protein is needed to fully activate p53. Disturbance of the interplay between p53 and VHL seems to explain the lack of efficient response to chemotherapy in RCC. Moreover, it has been observed that changes in the expression of p53 isoforms are associated with different stages of RCC and overall survival. Thus, herein, an attempt was made to answer the question whether p53 and its isoforms are important factors in the development of RCC on the one hand, and in positive response to anti-RCC therapy on the other hand.

The Underestimated Role of the p53 Pathway in Renal Cancer

“…Indeed, in normoxic condition, hydroxylation by prolyl hydroxylases (PHDs) of HIF-1α in its oxygen-dependent degradation domain (ODD) is required for the interaction of HIF-1α with VHL, leading to the ubiquitination and proteasomal degradation of HIF-1α. When the cells are hypoxic, PHDs are inactivated, this leads to HIF-1α stabilization and translocation to the nucleus, where it forms a dimer with HIF-1β and binds and promotes the expression of genes involved in a series of cellular responses, including survival, cell death, metabolic reprogramming, angiogenesis, stemness, inflammation, metastasis, immune evasion, etc., that is, genes that help tumor cells to adapt to the hypoxic environment and contribute to tumor progression [ 13 , 14 ]. Meanwhile, p53 responds to several cellular stresses including hypoxia, and the loss of p53 functions and hypoxia are two common events in cancer progression, indicating a close but complex interplay between p53 and HIF1α [ 15 ].…”

“…In chRCC, the highest rate of mutations (frameshifts, missense and nonsense mutations) is observed at position R213. In ccRCC the highest frequency of mutations are in G244, R273, P278, K132 and C135 codons [ 14 ].…”

“…It has been reported that VHL protein is required to fully activate p53 functions, and the perturbation of the interplay between p53 and VHL seems to explain the resistance of RCCs to chemotherapy [ 14 ]. Moreover, in many tumors that have mutations in the VHL gene, the expression of the proteins involved in p53 stability and activity is deregulated, and as a consequence, p53 is not functional despite its wild-type status, suggesting that VHL and p53 activities are somehow dependent on each other in the cell.…”