p53 ubiquitination: Mdm2 and beyond

Abstract

Although early studies have suggested that the oncoprotein Mdm2 is the primary E3 ubiquitin ligase for the p53 tumor suppressor, an increasing amount of data suggests that p53 ubiquitination and degradation are more complex than once thought. The discoveries of MdmX, HAUSP, ARF, COP1, Pirh2, and ARF-BP1 continue to uncover the multiple facets of this pathway. There is no question that Mdm2 plays a pivotal role in downregulating p53 activities in numerous cellular settings. Nevertheless, growing evidence challenges the conventional view that Mdm2 is essential for p53 turnover.

Figure 1. Ubiquitin Acts as a Specific Signal for the Nuclear Export of p53

H1299 cells were transfected with HA-p53-Ub, HA-p53-SUMO1, and HA-p53-Nedd8 expression constructs. Twenty-four hours posttransfection, the cells were fixed with 4% paraformaldehyde and immunofluorescence was done with anti-HA monoclonal antibody and DAPI.

Figure 2. A Model for the Role of Mdm2 in Cell Survival

In unstressed cells, low levels of Mdm2 only induce monoubiquitination of p53, which is not sufficient for degradation, whereas ARF-BP1 may be the major E3 ligase responsible for p53 ubiquitination and degradation. Upon DNA damage, p53 becomes stabilized and activated by posttranslational modifications and other signaling pathways, which lead to induction of hdm2, COP1, and pirh2 genes (see text for details).

Figure 3. ARF-BP1 Is Evolutionarily Conserved

(A) A table of E3 ubiquitin ligases specific for p53. The genomes of H. sapiens, M. musculus, D. melanogaster, and C. elegans were screened for putative homologs of the indicated genes with BLASTP using the NCBI genebank. A putative ARF-BP1 gene was found in both D. melanogaster (CG8184-PB; gi 24642255) and C. elegans (Y67D8C.5; gi 71999446) (see text for details). (B) A schematic of functional domains for the ARF-BP1 genes found in human, mouse, and putative genes found in C. elegans and D. melanogaster. Abbreviations: ARLD1, armadillo-like repeats 1 (also called DUF908, domain of unknown function); ARLD2, armadillo-like repeats 2 (also called DUF913, domain of unknown function); UBA, ubiquitin-associated domain; and WWE, domain occurring in two functional classes of proteins, namely those involved in ubiquitination and those involved in poly-ADP ribosylation. This name is derived from two conserved Trp residues (W) followed by a Glu residue (E); HECT, homologous to E6AP C-terminal domain.