Misfolding, Aggregation, and Disordered Segments in c-Abl and p53 in Human Cancer

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.

Keywords: cancer; kinases; misfolding; signaling; tumor suppressor.

Figure 1

Schematic representation of cellular guardians. Tumor suppressors, chaperones, and kinases represent genome, proteome, and interactome examples of cellular guardians, respectively. The maintenance of tumorigenic processes is commonly achieved via new co-alliances and the transformation of different guardians. The hallmarks of cancer were highlighted in the scheme.

Figure 2

Prion-like effects of mutated p53. The seeding of mutated p53 (p53^Mut) accelerates the amyloidogenic aggregation of wild-type p53 (p53^WT) and may result in the co-aggregation of different cellular partners including p53 homologs p63 and p73, heat shock proteins (Hsps), and the p53 regulator Mdm2, and may also include additional proteins (?) that have yet to be discovered. Aggregation leads p53 to lose or gain oncogenic function.

Figure 3

c-Abl architecture is complex and not fully understood. Schematic representation of full-length c-Abl showing crystal structures of the core (PDB ID: 1OPK), F-actin-binding domain – FABD (PDB ID: 1ZZP), and flexible segments at the N- (N-Cap) and C-terminal regions (proline–any residue–any residue–Proline, i.e., PxxP motifs, nuclear localization signals – NLS, and DNA-binding domain – DBD). The linker regions in the core are colored red. The cellular partners of specific domains are shown in brackets. The myristate switch (sphere representation) is presented in the open (dashed orange line) and closed (solid orange line) states.

Figure 4

Intracellular signaling of c-Abl. A schematic representation of the broad spectrum of c-Abl signaling pathways in different sub-cellular compartments. The nuclei are shown by dashed lines. Inactivated c-Abl, Rb, p53, Mdm2, and PLC_γ-1 proteins are colored black to distinguish them from activated forms (represented in different colors). “P” in red means phosphorylation, “Ub” in yellow ubiquitination, “Ac” in light red acetylation, and the yellow ray is genotoxic stress. Red and black arrows represent signaling through phosphorylation and promoting activity, respectively, and red lines with a crossbar indicate signaling inhibition. Molecules anchored to the membrane are: PI(4,5)P₂ – phosphatidylinositol-4,5-biphosphate, Myr – myristate, and DAG – diacylglycerol.