Regulation activity is inhibited by ARF. ARF-BP1 directly

Regulation of Arf at protein levels Althoughthe importance of Arf in cellular senescence and tumor suppression is well-documented,studies about its posttranslational regulation is limited.  A report from the Sherr’s lab suggested that Arf,which has no lysine sites, is polyubiquitinated at its N-terminus followed byproteasomal degradation by an unknown E3-ubiquitin ligase (23).  Then a number of ubiquitin ligases have beenisolated that regulate Arf at the protein level.  In short, both transcriptional andpost-transcriptional controls are important in Arf regulation. In 2005, Chen et al. identified an ubiquitinligase, ARF-BP1, as a key factor associated with ARF in vivo (65).  ARF-BP1 harborsa signature HECT motif, and its ubiquitin ligase activity is inhibited by ARF.

 ARF-BP1 directly bound and ubiquitinated p53; they alsoreported that inactivation of endogenous ARF-BP1 wascrucial for ARF-mediated p53 stabilization.  Thus, their study revealed that ARF-BP1 is a critical mediator of both the p53-dependentand p53-independent tumor suppressor functions of ARF.  In 2010, the same group reported the firstE3-ubiquitin ligase for ARF named ULF (ubiquitin ligase for Arf:ULF) (66).  ULF inducespolyubiquitination and proteasomal degradation of ARF, thus activating cellproliferation.

 ULF interacts with ARF both in vitro and in vivo and promotes the lysine-independent ubiquitylation anddegradation of ARF (66).  ULF knockdown stabilizes ARF in normal human cells, triggering ARF-dependent, p53-mediatedgrowth arrest.  NPM, amultifunctional protein, forms a stable protein complex with ARF (66) in thenucleolus, protects ARF from proteasome-mediated degradation.  NPMand c-Myc, both of which are commonly overexpressed in cancer cells, promoted ARF stabilization in cancer cells by abrogatingULF-mediated ARF ubiquitylation (66, 67). NPM is mutated in about one third of acutemyeloid leukemia (AML) patients, which leads to aberrant cytoplasmicdislocation of the protein.  CytoplasmicNPM mutants lose their abilities to retain ARF inthe nucleolus and thus unable to stabilize Arf,compromising the activation of the ARF-p53 pathway(68).  The steady levels of both Arf and p53 are very low in human AML cells expressing cytoplasmicNPM.  ULF knockdown stabilized ARF and reactivated p53 responses in AML cells,suggesting that ULF is a bone fide E3 ligase for ARF.

 Hence they suggested a novel therapeuticapproach of AML by inhibiting ULF (68). Tumor necrosis factor receptor (TNFR) -associated death domain (TRADD) protein is a central adaptor in the TNFR1signaling complex that mediates both cell death and inflammatory signals.  Chio II et al. (69) reported that TRADDshuttled dynamically from the cytoplasm into the nucleus to modulate theinteraction between Arf and ULF, thereby promotingArf protein stability and tumor suppression.  The ULF-mediated degradation of Arf isfurther regulated by NPM and c-Myc, suggesting that Myc regulates Arf bothtranscriptionally and translationally (69).  Arfstability control is crucial for differentiating normal (low) versus oncogenic(high) levels of c-Myc expression, and suggests that differential effects onULF-mediated Arf ubiquitination by c-Myc levelsact as a barrier in oncogene-induced stress responses (69). Koand colleagues reported a second E3-ubiquitin ligase, Makorin 1 (MKRN1), whichtargets Arf (70).

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 MKRN1 knockout MEFs presented decreased cell growth withconcomitant increase in the ARF protein levels (70).  Consistent with these findings, MKRN1 wasshown to induce ubiquitination and proteasomal degradation of Arf (71).