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
Non-small cell lung cancer (NSCLC) is often characterized by mutually exclusive mutations in the epidermal growth factor receptor (EGFR) or the guanosine
triphosphatase
KRAS. We hypothesized that blocking EGFR palmitoylation, previously shown to inhibit EGFR activity, might alter downstream signaling in the KRAS-mutant setting. Here, we found that blocking EGFR palmitoylation, by either knocking down the palmitoyltransferase DHHC20 or expressing a palmitoylation-resistant EGFR mutant, reduced activation of the kinase PI3K, the abundance of the transcription factor
MYC
, and the proliferation of cells in culture, as well as reduced tumor growth in a mouse model of KRAS-mutant lung adenocarcinoma. Knocking down DHHC20 reduced the growth of existing tumors derived from human KRAS-mutant lung cancer cells and increased the sensitivity of these cells to a PI3K inhibitor. Palmitoylated EGFR interacted with the PI3K regulatory subunit PIK3R1 (p85) and increased the recruitment of the PI3K heterodimer to the plasma membrane. Alternatively, blocking palmitoylation increased the association of EGFR with the MAPK adaptor Grb2 and decreased that with p85. This binary switching between MAPK and PI3K signaling, modulated by EGFR palmitoylation, was only observed in the presence of oncogenic KRAS. These findings suggest a mechanism whereby oncogenic KRAS saturates signaling through unpalmitoylated EGFR, reducing formation of the PI3K signaling complex. Future development of DHHC20 inhibitors to reduce EGFR-PI3K signaling could be beneficial to patients with KRAS-mutant tumors.
...
PMID:Blocking EGFR palmitoylation suppresses PI3K signaling and mutant KRAS lung tumorigenesis. 3212 96
