Abstract
The current understanding of the molecular mechanisms that lead to cancer is not sufficient to explain the loss or gain of function in proteins related to tumorigenic processes. Among them, more than 100 oncogenes, 20–30 tumor-suppressor genes, and hundreds of genes participating in DNA repair and replication have been found to play a role in the origins of cancer over the last 25 years. The phosphorylation of serine, threonine, or tyrosine residues is a critical step in cellular growth and development and is achieved through the tight regulation of protein kinases. Phosphorylation plays a major role in eukaryotic signaling as kinase domains are found in 2% of our genes. The deregulation of kinase control mechanisms has disastrous consequences, often leading to gains of function, cell transformation, and cancer. The c-Abl kinase protein is one of the most studied targets in the fight against cancer and is a hotspot for drug development because it participates in several solid tumors and is the hallmark of chronic myelogenous leukemia. Tumor suppressors have the opposite effects. Their fundamental role in the maintenance of genomic integrity has awarded them a role as the guardians of DNA. Among the tumor suppressors, p53 is the most studied. The p53 protein has been shown to be a transcription factor that recognizes and binds to specific DNA response elements and activates gene transcription. Stress triggered by ionizing radiation or other mutagenic events leads to p53 phosphorylation and cell-cycle arrest, senescence, or programed cell death. The p53 gene is the most frequently mutated gene in cancer. Mutations in the DNA-binding domain are classified as class I or class II depending on whether substitutions occur in the DNA contact sites or in the protein core, respectively. Tumor-associated p53 mutations often lead to the loss of protein function, but recent investigations have also indicated gain-of-function mutations. The prion-like aggregation of mutant p53 is associated with loss-of-function, dominant-negative, and gain-of-function effects. In the current review, we focused on the most recent insights into the protein structure and function of the c-Abl and p53 proteins that will provide us guidance to understand the loss and gain of function of these misfolded tumor-associated proteins.
Highlights
The current understanding of the molecular mechanisms that lead to cancer is not sufficient to explain the loss or gain of function in proteins related to tumorigenic processes
The c-Abl kinase protein is one of the most studied targets in the fight against cancer and is a hotspot for drug development because it participates in several solid tumors and is the hallmark of chronic myelogenous leukemia
Stress triggered by ionizing radiation or other mutagenic events leads to p53 phosphorylation and cell-cycle arrest, senescence, or programed cell death
Summary
The fundamental dogma in biology for all living organisms dictates that DNA becomes RNA through the transcriptional machinery, and this step is followed by the translation of RNA to specific proteins. The pattern of hydrophobic and polar residues in a specific amino acid sequence dictates the preferential contacts and the fingerprint for protein folding and dynamics These key elements are likely selected and optimized during protein evolution to ensure sampling of a restricted number of conformations and ensure that proteins are “minimally frustrated” [7]. Depending on the protein architecture and secondary content, small proteins (60–100 residues) may be converted from their unfolded to their native states without populating long-lived intermediate states (two-state equilibrium) Those with more than approximately 100 residues or that are composed of at least two globular domains commonly populate intermediate states during the folding process. We focus on the c-Abl and p53 proteins and shed light on the involvement of incorrect conformations in amyloid formation and the triggering of cell malignancy and cancer progression
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