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:2.1.1.37 (
DNA methyltransferase
)
4,983
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 core components of regenerative medicine are stem cells with high self-renewal and tissue regeneration potentials. Adult stem cells can be obtained from many organs and tissues.
NANOG
,
SOX2
and
OCT4
represent the core regulatory network that suppresses differentiation-associated genes, maintaining the pluripotency of mesenchymal stem cells. The roles of
NANOG
in maintaining self-renewal and undifferentiated status of adult stem cells are still not perfectly established. In this study we define the effects of downregulation of
NANOG
in maintaining self-renewal and undifferentiated state in mesenchymal stem cells (MSCs) derived from subcutaneous adipose tissue (hASCs). hASCs were expanded and transfected in vitro with short hairpin Lentivirus targeting
NANOG
. Gene suppressions were achieved at both transcript and proteome levels. The effect of
NANOG
knockdown on proliferation after 10 passages and on the cell cycle was evaluated by proliferation assay, colony forming unit (CFU), qRT-PCR and cell cycle analysis by flow-cytometry. Moreover,
NANOG
involvement in differentiation ability was evaluated. We report that downregulation of
NANOG
revealed a decrease in the proliferation and differentiation rate, inducing cell cycle arrest by increasing
p27
/
CDKN1B
(Cyclin-dependent kinase inhibitor 1B) and
p21
/
CDKN1A
(Cyclin-dependent kinase inhibitor 1A) through
p53
and regulate
DLK1
/
PREF1
. Furthermore,
NANOG
induced downregulation of
DNMT1
, a major
DNA methyltransferase
responsible for maintaining methylation status during DNA replication probably involved in cell cycle regulation. Our study confirms that
NANOG
regulates the complex transcription network of plasticity of the cells, inducing cell cycle arrest and reducing differentiation potential.
...
PMID:Knockdown of NANOG Reduces Cell Proliferation and Induces G0/G1 Cell Cycle Arrest in Human Adipose Stem Cells. 3113 Jun 93
