Regulation activity is inhibited by ARF. ARF-BP1 directly

Regulation of Arf at protein levels


the 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 by
proteasomal degradation by an unknown E3-ubiquitin ligase (23).  Then a number of ubiquitin ligases have been
isolated that regulate Arf at the protein level.  In short, both transcriptional and
post-transcriptional controls are important in Arf regulation.


In 2005, Chen et al. identified an ubiquitin
ligase, ARF-BP1, as a key factor associated with ARF in vivo (65).  ARF-BP1 harbors
a signature HECT motif, and its ubiquitin ligase activity is inhibited by ARF.  ARF-BP1 directly bound and ubiquitinated p53; they also
reported that inactivation of endogenous ARF-BP1 was
crucial for ARF-mediated p53 stabilization.  Thus, their study revealed that ARF-BP1 is a critical mediator of both the p53-dependent
and p53-independent tumor suppressor functions of ARF.  In 2010, the same group reported the first
E3-ubiquitin ligase for ARF named ULF (ubiquitin ligase for Arf:
ULF) (66).  ULF induces
polyubiquitination and proteasomal degradation of ARF, thus activating cell
proliferation.  ULF interacts with ARF both in vitro and in vivo and promotes the lysine-independent ubiquitylation and
degradation of ARF (66).  ULF knockdown stabilizes ARF in normal human cells, triggering ARF-dependent, p53-mediated
growth arrest.  NPM, a
multifunctional protein, forms a stable protein complex with ARF (66) in the
nucleolus, protects ARF from proteasome-mediated degradation.  NPM
and c-Myc, both of which are commonly overexpressed in cancer cells, promoted ARF stabilization in cancer cells by abrogating
ULF-mediated ARF ubiquitylation (66, 67).


NPM is mutated in about one third of acute
myeloid leukemia (AML) patients, which leads to aberrant cytoplasmic
dislocation of the protein.  Cytoplasmic
NPM mutants lose their abilities to retain ARF in
the 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 cytoplasmic
NPM.  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 therapeutic
approach of AML by inhibiting ULF (68).


Tumor necrosis factor receptor (TNFR) –
associated death domain (TRADD) protein is a central adaptor in the TNFR1
signaling complex that mediates both cell death and inflammatory signals.  Chio II et al. (69) reported that TRADD
shuttled dynamically from the cytoplasm into the nucleus to modulate the
interaction between Arf and ULF, thereby promoting
Arf protein stability and tumor suppression.  The ULF-mediated degradation of Arf is
further regulated by NPM and c-Myc, suggesting that Myc regulates Arf both
transcriptionally and translationally (69).  Arf
stability control is crucial for differentiating normal (low) versus oncogenic
(high) levels of c-Myc expression, and suggests that differential effects on
ULF-mediated Arf ubiquitination by c-Myc levels
act as a barrier in oncogene-induced stress responses (69).


and colleagues reported a second E3-ubiquitin ligase, Makorin 1 (MKRN1), which
targets Arf (70).  MKRN1 knockout MEFs presented decreased cell growth with
concomitant increase in the ARF protein levels (70).  Consistent with these findings, MKRN1 was
shown to induce ubiquitination and proteasomal degradation of Arf (71).

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