Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UNIPROT:P62988 (
Ubiquitin
)
4,326
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
We have sought to determine whether insulin-like growth factor I (IGF-I) regulates the levels of
insulin receptor substrate-1
(
IRS-1
) in prostate epithelial cells. Exposure of prostate epithelial cells to IGF-I in the absence of other growth factors leads to a reduction in
IRS-1
levels.
Ubiquitin
content of
IRS-1
is increased in the presence of IGF-I, and inhibitors of the proteasome prevented the reduction of
IRS-1
levels seen following IGF-I exposure. These results imply that
IRS-1
is targeted to the proteasome upon exposure to IGF-I. The addition of epidermal growth factor (EGF) maintained
IRS-1
levels even in the presence of IGF-I and inhibits IGF-I-dependent ubiquitination of
IRS-1
. Thus, these two growth factors, IGF-I and EGF, had antagonistic effects on
IRS-1
protein levels in prostate epithelial cells. This regulation of
IRS-1
reveals a novel level of cross-talk between the IGF-I and EGF signal pathways, which may have implications in tumors that harbor activating mutations in the EGF receptor.
...
PMID:Insulin-like growth factor I-mediated degradation of insulin receptor substrate-1 is inhibited by epidermal growth factor in prostate epithelial cells. 1081 32
Muscle atrophy is a consequence of chronic diseases (e.g., diabetes) and glucocorticoid-induced insulin resistance that results from enhanced activity of the ubiquitin-proteasome pathway. The PI3K/Akt pathway inhibits the FOXO-mediated transcription of the muscle-specific E3 ligase atrogin-1/MAFbx (AT-1), whereas the MEK/ERK pathway increases Sp1 activity and ubiquitin (
UbC
) expression. The observations raise a question about how the transcription of these atrogenes is synchronized in atrophic muscle. We tested a signaling model in which FOXO3a mediates crosstalk between the PI3K/Akt and MEK/ERK pathways to coordinate AT-1 and
UbC
expression. In rat L6 myotubes, dexamethasone (> or = 24 h) reduced insulin receptor substrate (IRS)-1 protein and PI3K/Akt signaling and increased AT-1 mRNA. IRS-2 protein, MEK/ERK signaling, Sp1 phosphorylation, and
UbC
transcription were simultaneously increased. Knockdown of
IRS-1
using small interfering RNA or adenovirus-mediated expression of constitutively activated FOXO3a increased IRS-2 protein, MEK/ERK signaling, and
UbC
expression. Changes in PI3K/Akt and MEK/ERK signaling were recapitulated in rat muscles undergoing atrophy due to streptozotocin-induced insulin deficiency and concurrently elevated glucocorticoid production.
IRS-1
and Akt phosphorylation were decreased, whereas MEK/ERK signaling and expression of IRS-2,
UbC
and AT-1 were increased. We conclude that FOXO3a mediates a reciprocal communication between the
IRS-1
/PI3K/Akt and IRS-2/MEK/ERK pathways that coordinates AT-1 and ubiquitin expression during muscle atrophy.
...
PMID:FOXO3a mediates signaling crosstalk that coordinates ubiquitin and atrogin-1/MAFbx expression during glucocorticoid-induced skeletal muscle atrophy. 2037 24
