Balance of Yin and Yang: ubiquitylation-mediated regulation of p53 and c-Myc - PubMed (original) (raw)

Review

Balance of Yin and Yang: ubiquitylation-mediated regulation of p53 and c-Myc

Mu-Shui Dai et al. Neoplasia. 2006 Aug.

Abstract

Protein ubiquitylation has been demonstrated to play a vital role not only in mediating protein turnover but also in modulating protein activity. The stability and activity of the tumor suppressor p53 and of the oncoprotein c-Myc are no exception. Both are regulated through independent ubiquitylation by several E3 ubiquitin ligases. Interestingly, p53 and c-Myc are functionally connected by some of these E3 enzymes and their regulator ARF, although these proteins play opposite roles in controlling cell growth and proliferation. The balance of this complex ubiquitylation network and its disruption during oncogenesis will be the topics of this review.

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Figures

Figure 1

A diagram showing that multiple ubiquitin E3 ligases target p53 for ubiquitylation. Bars indicate ubiquitylation and the functional suppression of p53, whereas arrows indicate the transcriptional activation of the ubiquitin E3 ligase by p53.

Figure 2

A schematic diagram showing the functional domains of the c-Myc protein and its regulation by multiple ubiquitin E3 ligases. c-Myc contains an N-terminal TAD, as well as C-terminal basic (B), helix-loop-helix (HLH), and leucine zipper (LZ) domains. The central domain contains a PEST region. There are two conserved MBI and MBII motifs located in the TAD. Two phosphorylation residues, T58 and S62, are shown. Fbw7 binds to MBI and ubiquitylates c-Myc in a T58 phosphorylation-dependent manner. Skp2 targets c-Myc for ubiquitylation through both the MBII and C-terminal domains. ARF-BP1/HectH9 ubiquitylates one or more of six lysine (K) residues around the NLS region by binding to TAD. Ubiquitylation by SCFFbw7 results in the degradation of c-Myc, whereas ubiquitylation by SCFSkp2 and HectH9/ARF-BP1 leads to the activation of c-Myc.

Figure 3

A diagram showing growth signal-mediated c-Myc phosphorylation and ubiquitylation pathways. Growth signals such as serum stimulation activate RAS. The RAS/Raf/MEK/ERK kinase cascade phosphorylates c-Myc at S62. The RAS-PI3K/Akt cascade inhibits GSK3_β_ activity. GSK3_β_ mediates the phosphorylation of c-Myc at T58. Phosphorylation of T58 recruits the Pin 1 prolyl isomerase, which may catalyze cis-trans isomerization at the P63 bond. This conformational change facilitates the targeting of c-Myc by PP2A phosphatase, which dephosphorylates c-Myc at S62. Phosphorylation of T58 and dephosphorylation of S62 serve as signals that trigger subsequent ubiquitylation and degradation of c-Myc by the SCFFbw7 complex.

Figure 4

Regulation of p53 and c-Myc transcription factors by nucleolar proteins. Bars indicate inhibition; arrows denote the functional activation of c-Myc.

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Balance of Yin and Yang: ubiquitylation-mediated regulation of p53 and c-Myc - PubMed (original) (raw)