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Review
. 2006 Aug;8(8):655-66.
doi: 10.1593/neo.06439.

Ubiquitin and ubiquitin-like modifications of the p53 family

Ian R Watson  1 , Meredith S Irwin
Affiliations
Review

Ubiquitin and ubiquitin-like modifications of the p53 family

Ian R Watson et al. Neoplasia. 2006 Aug.

Abstract

Regulation of p53 by the ubiquitin-proteasomal pathway has been studied considerably. Studies have also demonstrated that the ubiquitin-like proteins SUMO-1 and NEDD8 modify p53. Similarly, p63 and p73 are subject to regulation by ubiquitin and ubiquitin-like modifications, and perturbations of these pathways in the regulation of the p53 family have been implicated in tumorigenesis and developmental abnormalities. Here, we provide an overview of the current understanding of the regulation of the p53 family by covalent modification by ubiquitin, SUMO-1, and NEDD8.

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Figures

Figure 1
Figure 1
Schematic representation of the gene structure of the p53 family. The approximate exon regions encoding the unique amino acids for ΔN isoforms (orange), TA domain (TAD; red), DNA binding (DBD; blue), oligomerization (OD; yellow), and SAM domains (green) are indicated by color. Untranslated regions are shaded black. Arrows indicate transcriptional start sites. (A) The C-terminal splicing patterns generating full-length p53α, p53β, p53γ, and Δp53 are shown. The p53 isoforms that include the entire TA domain are transcribed from P1 and the recently described P1′ transcription initiations sites, and Δ 133p53 is transcribed from the P2 promoter located within intron 4. The alternative N-terminal splicing of intron 2 is indicated. (B) The C-terminal splicing patterns generating p73α, p73β, p73γ, p73δ, and p73ɛ are shown. The ΔNp73 isoforms are transcribed from the P2 promoter located within intron 3 (designated exon 3′). The alternative N-terminal splicing generating ΔEx2p73 and ΔEx2/3p73 is indicated. (C) The C-terminal splicing patterns generating p63α, p63β, and p63γ are shown. The ΔNp63 isoforms are transcribed from the P2 promoter located within intron 3 (designated as exon 3′). Exon size and approximate contribution of exons to the indicated functional domains are not drawn to scale.
Figure 2
Figure 2
General overview of the ubiquitin and UBL protein conjugation pathways. (1) Ubiquitin, SUMO, and NEDD8 are synthesized as precursors that are processed at a conserved C-terminal glycine residue by the hydrolase activity of deubiquitinating, desumoylating, and deneddylating enzymes, generating an exposed Gly-Gly motif that serves as the attachment site to target substrates. (2) The exposed C-terminal glycine of ubiquitin/SUMO/NEDD8 is adenylated by an activating (E1) enzyme in an ATP-dependent manner and is transferred to an active E1 cysteinyl side chain through a thiol ester linkage. (3) Activated ubiquitin/SUMO/NEDD8 is subsequently transferred to a conjugating (E2) enzyme, forming another thiol ester linkage. (4) A ligase (E3) transfers ubiquitin/SUMO/NEDD8 to the ɛ amino group of a substrate lysyl residue of target substrates, resulting in the formation of an isopeptide bond.
Figure 3
Figure 3
Lysyl residues modified by ubiquitin and UBL proteins. The known lysines modified by ubiquitin (Ub), SUMO-1 (S1), and NEDD8 (N8) are indicated for the p53 family. Approximate binding regions of the E2-conjugating enzymes and E3 ligases are shown. (A) Mdm2 ubiquitinates multiple p53 C-terminal lysines (K370, K372, K373, K381, K382, and K386), as well as additional lysines located in the DNA-binding domain (K101, K120, K132, and K139) [139]. The specific lysines ubiquitinated by Pirh2, COP1, and ARF-BP1, and the binding regions of COP1 and ARF-BP1 have not been reported. Mdm2 also promotes NEDD8 (N8) modification of at least three C-terminal lysines (K370, K372, and K373). p53 is sumoylated at K386 by PIAS1 and PIASxβ. (B) PIAS1 binds all p73 isoforms, but only TAp73α and ΔNp73α contain the lysine residue (627) that is sumoylated. NEDL2 and Itch bind the second C-terminal proline-rich (PY) motif; however, the specific lysines ubiquitinated by these HECT E3 ubiquitin ligases are not known. (C) p63α is sumoylated at lysine 637. A secondary sumoylation site has been reported at lysine 549. NEDD4 binds to the C-terminal PY motif of p63. Studies employed yeast two-hybrid screen, in vitro binding, and coimmunoprecipitation assays, or a combination of the abovementioned techniques, to determine the binding domains shown in the figure, and specific studies are referenced in the manuscript.
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