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POST-TRANSLATIONAL MODIFICATION OF p53 IN TUMORIGENESIS
Ann M. Bode and Zigang Dong
Abstract | Interest in the tumour suppressor p53 has generated much information regarding the complexity of its function and regulation in carcinogenesis. However, gaps still exist in our knowledge regarding the role of p53 post-translational modifications in carcinogenesis and cancer prevention. A thorough understanding of p53 will be extremely useful in the development of new strategies for treating and preventing cancer, including restoration of p53 function and selective killing of tumours with mutant TP53.
26S PROTEASOME
The protease part of the ubiquitin system, which is the main proteolytic system in eukaryotic cells that degrades polyubiquitylated proteins.
GLYCOSYLATION
The linkage of carbohydrates to protein either through the amide group of aspargine (N-glycosidic linkage) or through the hydoxyl of serine or threonine (O-glycosidic linkage).
RIBOSYLATION
The attachment of poly(ADPribose) chains to proteins catalysed by the nuclear protein poly(ADP-ribosyl) transferase. Ribosylation contributes to the regulation of DNA repair and transcription. Ribosylation of transcription factors prevents their binding to DNA.
The function of the p53 protein has proven to be much more intricate than anticipated by most scientists. The p53 tumour suppressor is a tightly regulated protein that acts by stopping cell-cycle progression or promoting apoptosis when cells encounter stress stimuli such as oncogene activation or DNA damage. Having a short half-life, p53 is normally maintained at low levels in unstressed mammalian cells by continuous ubiquitylation and subsequent degradation by the 26S PROTEASOME.This is
primarily due to the interaction of p53 with the RING-finger ubiquitin E3 ligase MDM2 (also known as HDM2). When the cell is confronted with stress, however, p53 ubiquitylation is suppressed and p53 is stabilized and accumulates in the nucleus, where it forms a homotetrameric complex1. Only tetrameric p53 seems to be fully active as a transcriptional activator or repressor of distinct target genes that contain p53 sequence-specific DNA binding sites2.Of the 150 genes targeted by p53, most are associated with regulation of cell-cycle arrest, apoptosis and/or DNA-repair processes (FIG. 1) processes that function to prevent proliferation of damaged cells. Although primarily a nuclear protein, p53 might function outside the nucleus through protein protein interactions. For example, p53 can translocate to the mitochondria, where it interacts directly with anti-apoptotic proteins such as BCL2...