Abstract
Missense mutations in the TP53 gene are among the most frequent alterations in human cancer. Consequently, many tumors show high expression of p53 point mutants, which may acquire novel activities that contribute to develop aggressive tumors. An unexpected aspect of mutant p53 function was uncovered by showing that some mutants can increase the malignant phenotype of tumor cells through alteration of the mevalonate pathway. Among metabolites generated through this pathway, isoprenoids are of particular interest, since they participate in a complex process of posttranslational modification known as prenylation. Recent evidence proposes that mutant p53 also enhances this process through transcriptional activation of ICMT, the gene encoding the methyl transferase responsible for the last step of protein prenylation. In this way, mutant p53 may act at different levels to promote prenylation of key proteins in tumorigenesis, including several members of the RAS and RHO families. Instead, wild type p53 acts in the opposite way, downregulating mevalonate pathway genes and ICMT. This oncogenic circuit also allows to establish potential connections with other metabolic pathways. The demand of acetyl-CoA for the mevalonate pathway may pose limitations in cell metabolism. Likewise, the dependence on S-adenosyl methionine for carboxymethylation, may expose cells to methionine stress. The involvement of protein prenylation in tumor progression offers a novel perspective to understand the antitumoral effects of mevalonate pathway inhibitors, such as statins, and to explore novel therapeutic strategies.
Highlights
TP53, the gene encoding the tumor suppressor p53, is one of the most frequently mutated genes in human cancer [1]
Several metabolites produced by the MVA pathway may affect cell behavior, the positive effect of mutant p53 on the expression of MVA pathway genes and Isoprenylcysteine Carboxyl Methyltransferase (ICMT) underline the relevance of isoprenoids in cancer
The negative regulation exerted by wt p53 on Sterol Responsive Element Binding Proteins (SREBPs)-2 maturation and ICMT expression indicates that MVA pathway and carboxymethylation of prenylated proteins should be strictly regulated under physiological conditions
Summary
TP53, the gene encoding the tumor suppressor p53, is one of the most frequently mutated genes in human cancer [1]. The unexpected finding that mutant p53 alters the expression of mevalonate (MVA) pathway genes [7] opened new avenues to understand the importance of metabolism in tumor cell biology. The pathological role of alterations on the MVA pathway was initially proposed based on the observation that inhibitors of the enzyme that catalyzes the rate-limiting step (3-hydroxy-3methyl-glutaryl-CoA reductase, HMGCR), known as statins, reduced the proliferation of tumor cells [8, 9].
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