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: EC:3.6.1.25 (
triphosphatase
)
1,529
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Hepatocellular carcinoma often reactivates the genes that are transiently expressed in fetal or neonatal livers. However, the mechanism of their activation has not been elucidated. To explore how oncogenic signaling pathways could be involved in the process, we examined the expression of fetal/neonatal genes in liver tumors induced by the introduction of myristoylated v-akt murine thymoma viral oncogene (AKT), HRas proto-oncogene, guanosine
triphosphatase
(HRAS
V12
), and MYC proto-oncogene, bHLH transcription factor (Myc), in various combinations, into mouse hepatocytes
in vivo
. Distinct sets of fetal/neonatal genes were activated in HRAS- and HRAS/Myc-induced tumors: aldo-keto reductase family 1, member C18 (
Akr1c18
), glypican 3 (
Gpc3
), carboxypeptidase E (
Cpe
), adenosine triphosphate-binding cassette, subfamily D, member 2 (
Abcd2
), and trefoil factor 3 (
Tff3
) in the former; insulin-like growth factor 2 messenger
RNA binding protein
3 (
Igf2bp3
), alpha fetoprotein (
Afp
),
Igf2
, and H19, imprinted maternally expressed transcript (
H19
) in the latter. Interestingly, HRAS/Myc-induced tumors comprised small cells with a high nuclear/cytoplasmic ratio and messenger RNA (mRNA) expression of delta-like noncanonical Notch ligand 1 (
Dlk1
), Nanog homeobox (
Nanog
), and sex determining region Y-box 2 (
Sox2
). Both HRAS- and HRAS/Myc-induced tumors showed decreased DNA methylation levels of
Line1
and
Igf2
differentially methylated region 1 and increased nuclear accumulation of 5-hydroxymethylcytosine, suggesting a state of global DNA hypomethylation. HRAS/Myc-induced tumors were characterized by an increase in the mRNA expression of enzymes involved in DNA methylation (DNA methyltransferase [
Dnmt1
,
Dnmt3
]) and demethylation (ten-eleven-translocation methylcytosine dioxygenase 1 [
Tet1
]), sharing similarities with the fetal liver. Although mouse hepatocytes could be transformed by the introduction of HRAS/Myc
in vitro
, they did not express fetal/neonatal genes and sustained global DNA methylation, suggesting that the epigenetic alterations were influenced by the
in vivo
microenvironment. Immunohistochemical analyses demonstrated that human hepatocellular carcinoma cases with nuclear MYC expression were more frequently positive for AFP, IGF2, and DLK1 compared with MYC-negative tumors.
Conclusion:
The HRAS signaling pathway and its interactions with the Myc pathway appear to reactivate fetal/neonatal gene expression in hepatocytic tumors partly through epigenetic alterations, which are dependent on the tumor microenvironment.
...
PMID:Emergence of the Dedifferentiated Phenotype in Hepatocyte-Derived Tumors in Mice: Roles of Oncogene-Induced Epigenetic Alterations. 3106 57
The human mitochondrial ribosome (mitoribosome) and associated proteins regulate the synthesis of 13 essential subunits of the oxidative phosphorylation complexes. We report the discovery of a mitoribosome-associated quality control pathway that responds to interruptions during elongation, and we present structures at 3.1- to 3.3-angstrom resolution of mitoribosomal large subunits trapped during ribosome rescue. Release factor homolog C12orf65 (mtRF-R) and
RNA binding protein
C6orf203 (MTRES1) eject the nascent chain and peptidyl transfer RNA (tRNA), respectively, from stalled ribosomes. Recruitment of mitoribosome biogenesis factors to these quality control intermediates suggests additional roles for these factors during mitoribosome rescue. We also report related cryo-electron microscopy structures (3.7 to 4.4 angstrom resolution) of elongating mitoribosomes bound to tRNAs, nascent polypeptides, the guanosine
triphosphatase
elongation factors mtEF-Tu and mtEF-G1, and the Oxa1L translocase.
...
PMID:Elongational stalling activates mitoribosome-associated quality control. 3324 91
