Nuclear insulin-like growth factor binding protein-3 induces apoptosis and is targeted to ubiquitin/proteasome-dependent proteolysis
W. Zwerschke
Cell Metabolism & Differentiation Group, Institute for Biomedical Aging Research of the Austrian Academy of Sciences, Innsbruck, Austria
Insulin-like growth factor binding protein-3 (IGFBP-3), the product of
a tumor suppressor target gene, is associated with cellular senescence
and can induce apoptosis by IGF-I-dependent and -independent
mechanisms. IGFBP-3 controls the bioavailability of IGFs in the
extracellular environment and is known to be subject to degradation by
various extracellular proteases. We show here that IGFBP-3 exists as
nuclear protein in situ in human osteosarcoma tissue. Strikingly,
IGFBP-3 was predominantly localized in the nuclei of osteoid forming
osteosarcoma cells, but not detectable in chondroid forming
osteosarcoma cells. Concerning the mechanism by which the abundance of
nuclear IGFBP-3 could be regulated, we demonstrate for the first time
that nuclear IGFBP-3 is a direct target of
ubiquitin/proteasome-dependent degradation. We show that IGFBP-3
degradation depends on an active ubiquitin-E1-ligase, specific 26S
proteasome inhibitors can efficiently stabilize nuclear IGFBP-3, and
the metabolic half-life of nuclear IGFBP-3 is strongly reduced relative
to cytoplasmic IGFBP-3. Nuclear IGFBP-3 is highly polyubiquitinated at
multiple lysine residues in its conserved carboxyl-terminal domain and
stabilized through mutation of two Cterminal lysine residues. Moreover,
we demonstrate that IGFBP-3, if ectopically expressed in the nucleus,
can induce apoptotic cell death. These results suggest that
ubiquitin/proteasomemediated proteolysis of nuclear IGFBP-3 may
contribute to downregulation of apoptosis.
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