Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
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Enzyme
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Query: EC:3.1.3.16 (
calcineurin
)
17,112
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Autophagy-promoting proteins and stimuli are often associated with inhibition of cell proliferation; in this context, we recently described a key role for the pro-autophagic protein
AMBRA1
. Indeed,
AMBRA1
, through its direct interaction with the
protein phosphatase
PP2A, tightly regulates the stability of the oncoprotein and pro-mitotic factor c-Myc. Moreover, the
AMBRA1
-mediated regulation of c-Myc affects both cell proliferation rate and tumorigenesis. Interestingly,
AMBRA1
/PP2A activity is under the control of the master regulator of autophagy and cell growth, the protein kinase mTOR. Besides the mechanistic details of this regulation pathway which we dissected previously, any possible interplay(s) between
AMBRA1
and its interactor BECLIN 1 was not investigated in this scenario. Here we show that both
AMBRA1
and BECLIN 1 affect c-Myc regulation, but through two different pathways. Nevertheless, these two pro-autophagic proteins are, together with PP2A, in the same macromolecular complex, whose functional significance of which will be addressed in future studies.
...
PMID:AMBRA1 and BECLIN 1 interplay in the crosstalk between autophagy and cell proliferation. 2610 1
In zebrafish, two paralogous genes, activating molecule in beclin-1 (BECN1)-regulated autophagy
ambra1a
and
ambra1b
, both required for the autophagic process and during development, encode the protein
AMBRA1
, a positive regulator of early steps of autophagosome formation. As transcripts for both genes are expressed during embryogenesis in the heart region, in this work, we investigated the effects of
ambra1a
and
ambra1b
knockdown on heart development by means of morpholino oligonucleotides (MOs). Silencing of the two proteins by MOs directed against the ATG translation initiation codon affects cardiac morphogenesis, resulting in a small, string-like heart with pericardial edema, whereas treatment with splice-blocking MOs does not lead to overt cardiac phenotypes, thus revealing the relevance of maternally supplied
ambra1
transcripts for heart development. Co-injection of both ATG-MOs determines a more severe cardiac phenotype, with prominent pericardial edema. Whole-mount
in situ
hybridization (WMISH) for myosin light chain 7 (
myl7
), as well as
ambra1
ATG-MO microinjection in zebrafish transgenic line expressing green fluorescent protein in the heart, revealed defects with the heart jogging process followed by imperfect cardiac looping. Moreover, WMISH of homeodomain transcription factor 2 isoform c (
pitx2c
) transcripts showed both bilateral and reversed
pitx2c
expression in morphants. The morphants' cardiac phenotypes were effectively rescued by co-injection of MOs with human
AMBRA1
(
hAMBRA1
) messenger RNA (mRNA), pointing at the conservation of Ambra1 functions during evolution. Co-injections of
ambra1
ATG-MOs with a
hAMBRA1
mRNA mutated in the
protein phosphatase
2a (PP2A) binding sites (
hAMBRA1
PXP
) were not able to rescue the cardiac phenotypes, at the difference from wild-type
hAMBRA1
mRNA, and treatment of zebrafish embryos with the specific PP2A inhibitor cantharidin resulted in similar developmental cardiac defects. These results suggest a critical role for
AMBRA1
in vertebrate heart development, likely involving the binding site for the PP2A phosphatase.
...
PMID:Zebrafish
ambra1a
and
ambra1b
Silencing Affect Heart Development. 3232 Mar 44
