Let's Talk: p53 and Cancer
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The p53 protein is regulated when expressed through various processes that include:
phosphorylation, acetylation, methylation, ubiquitination, sumoylation, neddylation, glycosylation, ribosylation and O-GlcNAcylation.
For better perspective, let's look at some examples:
a) Ubiquitylation of p53 is critical for p53 control as it serves as a signal for degradation of the p53 protein.
b)Acetylation serves a crucial role in negatively regulating the functions of p53 as it increases the affinity of p53 to bind with its target proteins/ genes and controls the overall stability of p53.
These regulatory methods ensure that the p53 protein is degraded frequently and the p53 pathway remains dormant when the cell is functioning normally. When the DNA is damaged by factors such as ionization radiation, the p53 pathway is activated by kinase proteins.This is followed by the subsequent expression of p53 induced proteins. The expression and concentration of these p53 induced proteins ultimately dictate if the cell cycle is arrested, enabling time to conduct DNA repair or the cell is programmed to conduct apoptosis.
A detailed look at p53 pathway activation by Kinase for the nerdy student
A detailed look at p53 pathway activation by Kinase for the nerdy student
Kinase ATM is stimulated by the breakage of the double bond in DNA and Kinase Chk2 is in turn stimulated by ATM. These kinases phosphorylate the p53 protein at the amino terminal serine and threonine residues and inhibit it from binding to p53 target proteins, such as the MDM2. As the majority of p53 target genes contain a p53 binding site near the transcription start site (TSS), stabilizing the p53 protein at a high concentration allows the p53 to be covalently modified and bind to these target genes. In particular, the p53 recognizes the sequence RRRCWWGYYY (R: purine base, Y: pyrimidine base, W: adenine or thymine) inside the nucleus and combines with the sequence to form a tetramer.
Because p53 is so instrumental in conducting cell apoptosis, the down regulation of the p53 protein functionality would result in devastating consequences as it would halt p53 dependent growth arrests and apoptosis. In the case where cells mutate and become malignant,if p53 proteins are defective or if p53 activation is inhibited, they will not be able to swiftly conduct cell apoptosis and the cancer will spread. This is precisely why defective/inactivated p53 proteins can be identified in many cases of cancer.
For visual reference, check out this video:
Some Statistic
Some Statistic
p53 mutation spectrum from the TCGA lung squamous and lung adenocarcinoma datasets. A graphical representation is shown of the percent with p53 mutations (colored) versus wild-type p53 (gray). The mutations within a 5-residue stretch are grouped and colored to represent one of four hotspot regions,around amino acid 157 (orange), 175 (green), 248 (red), and 273 (yellow). Mutations outside of these four hotspots are grouped and colored blue.
Animesh Dali | DePauw University
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