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:1.14.99.3 (
heme oxygenase
)
4,196
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The robust induction of metallothionein-I and II (MT-I and MT-II) genes by several heavy metals such as zinc and cadmium requires the specific transcription factor
metal-responsive transcription factor 1
(
MTF1
). Chromium (VI), a major environmental carcinogen, not only failed to activate these genes but also inhibited their induction by Zn2+ or Cd2+. The heavy metal-induced expression of another
MTF1
target gene, zinc transporter 1 (ZnT-1), was also down-regulated by Cr6+. By contrast, the expression of two
MTF1
-independent Cd2+-inducible genes,
heme oxygenase
1 (HO-1) and HSP-70, was not sensitive to Cr6+. Cr6+ did not also affect the expression of housekeeping genes such as GAPDH or beta-actin. Stable cell lines overexpressing variable levels of
MTF1
, the key transactivator of the MT genes, demonstrated differential resistance toward the inhibitory effect of Cr6+, indicating
MTF1
as a target of chromium toxicity. The basal and inducible binding of
MTF1
to metal response elements was not affected by treatment of cells with Cr6+. Transient transfection studies showed that the ability of
MTF1
to transactivate the MT-I promoter was significantly compromised by Cr6+. The fusion protein consisting of a Gal-4 DNA binding domain and one or more of the three transactivation domains of
MTF1
, namely the acidic domain, proline-rich domain, and serine-threonine rich domain, activated the GAL-4-driven luciferase gene to different degrees, but all were sensitive to Cr6+.
MTF1
null cells were prone to apoptosis after exposure to Zn2+ or Cd2+ that was augmented in presence Cr6+, whereas the onset of apoptosis was significantly delayed in cells overexpressing
MTF1
.
...
PMID:Chromium(VI) down-regulates heavy metal-induced metallothionein gene transcription by modifying transactivation potential of the key transcription factor, metal-responsive transcription factor 1. 1271 93
