Beyond the Mevalonate Pathway: Control of Post-Prenylation Processing by Mutant p53

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.

Cysteine as a Multifaceted Player in Kidney, the Cysteine-Related Thiolome and Its Implications for Precision Medicine

“…Since cysteine can be converted to acetyl-CoA, it also allows the synthesis of coenzyme Q10 (CoQ10) (via the mevalonate pathway) [180], a key metabolite for preventing ferroptotic cell death [175,181], which is also associated with blood pressure control [182]. CoQ10 binds to the lipid peroxyl radicals, and together with the ferroptosis suppressing protein 1 (FSP1), the FSP1/CoQ10/NADPH axis represents a parallel system to the classical GPX4/glutathione to suppress lipid peroxidation and prevent ferroptosis [175,181].…”

Prenylation Defects and Oxidative Stress Trigger the Main Consequences of Neuroinflammation Linked to Mevalonate Pathway Deregulation

“…The farnesylated and geranyl-geranylated proteins, in fact, usually are subject to a proteolytic step, catalyzed by proteases, for example, the CAAX endopeptidase 1 (RCE1), which removes the residues of –AAX downstream of the prenylated Cys [ 42 ]. The modified cysteine is then methylated by a methyl transferase, such as isoprenylcysteine carboxymethyl transferase (ICMT), to produce a protein containing a C-term farnesyl cysteine methyl ester [ 43 ]. The farnesyl group confers a weak affinity for the membrane, so other modifications are necessary for the correct localization of the proteins [ 44 ].…”

Metabolic Reprogramming of Colorectal Cancer Cells and the Microenvironment: Implication for Therapy

“…Fatty acid synthesis was positively regulated by the mutant p53 through increasing the expression of key genes involved in fatty acid synthesis, such as the FASN gene [174]. Interestingly, the p53 mutant (R273H) has been found to elevate the expression of 17 mevalonate pathway genes involved in cholesterol and isoprenoid synthesis [175,176]. Moreover, p53-deficient CRC cancer cells activated the mevalonate pathway via SREBP2 [177].…”