Metallothionein is an HDAC regulated gene. It turns out zinc management
is part of the way certain HDAC inhibitors operate. I found this quite
interesting in light of the life-extending properties of metallothionein
variants that release more zinc. HDAC inhibitors have had
life-extending effects per se as well. Interesting connection.
Chem Biol. 2010 Jan 29;17(1):65-74.
Deacetylase Inhibitors Dissociate the Histone-Targeting ING2 Subunit
from the Sin3 Complex.
Smith KT, Martin-Brown SA, Florens L, Washburn MP, Workman JL.
Stowers Institute for Medical Research, Kansas City, MO 64110.
Histone deacetylase (HDAC) inhibitors are in clinical development for
several diseases, including cancers and neurodegenerative disorders.
HDACs 1 and 2 are among the targets of these inhibitors and are part of
multisubunit protein complexes. HDAC inhibitors (HDACis) block the
activity of HDACs by chelating a zinc molecule in their catalytic sites.
It is not known if the inhibitors have any additional functional effects
on the multisubunit HDAC complexes. Here, we find that suberoylanilide
hydroxamic acid (SAHA), the first FDA-approved HDACi for cancer, causes
the dissociation of the PHD-finger-containing ING2 subunit from the Sin3
deacetylase complex. Loss of ING2 disrupts the in vivo binding of the
Sin3 complex to the p21 promoter, an important target gene for cell
growth inhibition by SAHA. Our findings reveal a molecular mechanism by
which HDAC inhibitors disrupt deacetylase function. Copyright © 2010
Elsevier Ltd. All rights reserved.
PMID: 20142042 [PubMed - as supplied by publisher]
PMCID: PMC2819981 [Available on 2011/1/29]
Ann N Y Acad Sci. 2007 Nov;1119:129-46
Zinc, metallothioneins, and longevity--effect of zinc supplementation:
zincage study.
Mocchegiani E, Giacconi R, Cipriano C, Costarelli L, Muti E, Tesei S,
Giuli C, Papa R, Marcellini F, Mariani E, Rink L, Herbein G, Varin A,
Fulop T, Monti D, Jajte J, Dedoussis G, Gonos ES, Trougakos IP,
Malavolta M.
Immunology Center (Section: Nutrigenomic and Immunosenescence), Research
Department, Italian National Research Center on Ageing, Ancona, Italy.
Aging is an inevitable biological process that is associated with
gradual and spontaneous biochemical and physiological changes and
increased susceptibility to diseases. Because nutritional factors are
involved in improving immune functions, metabolic harmony, and
antioxidant defense, some nutritional factors, such as zinc, may modify
susceptibility to disease and promote healthy aging. In vitro (human
lymphocytes exposed to endotoxins) and in vivo (old or young mice fed
with low zinc dietary intake) studies revealed that zinc is important
for immune efficiency (innate and adaptive), antioxidant activity
(supeoxide dismutase), and cell differentiation via
clusterin/apolipoprotein J. Intracellular zinc homeostasis is regulated
by metallothioneins (MT) via ion release through the reduction of thiol
groups in the MT molecule. This process is crucial in aging because high
MT levels are not able to release zinc, resulting in low intracellular
free ion availability for biological functions. Improvement in these
functions occurs in the elderly after physiological zinc
supplementation. In this study, the selection of elderly subjects for
zinc supplementation is discussed in relation to the genetic background
of MT and pro-inflammatory cytokines, such as interleukin-6, because the
latter is involved both in MT-gene expression and in intracellular zinc
homeostasis.
Publication Types:
* Research Support, Non-U.S. Gov't
* Review
PMID: 18056962
in rat primary hepatocytes, sodium butyrate and Zn synergystically
increase MT more than either agent alone and more than the upregulation
of mRNA indicating post-translational effects; proprionate also
increased MT but no valeric acid, formate or acetate; dexamethasome is
also known to induce MT [PMID 1597404]
Zn2+ or sodium butyrate both overcome the inhibition on MT synthesis
when its promoter is methylated; Zn2+ activates the methylated promoter
of MT in mouse cell lines and butyrate overcomes the repression of the
thymidine kinase methylated promoter [PMID 1650472]
metallothioneins (MTs) are cysteine-rich stress response proteins that
scavenge reactive oxygen species and heavy metals; MT-I promoter is
methylated and suppressed in some solid and liquid tumors but can be
activated by treatment with inhibitors of DNA methyltransferase (DNMT)
and histone deacetylase (HDAC); ubiquitously expressed DNA
methyltransferase 1 (DNMT1) suppressed MT-I promoter activity
irrespective of its methylation status that does not require its
catalytic activity; DNMT1-mediated repression of MT-I promoter was
relieved by HDAC inhibitor trichostatin A; the methylated and
unmethylated MT-I promoter are differentially regulated by DNA
methyltransferase and methyl-CpG binding proteins, and DNMT1 could
suppress MT promoter by a transcriptional mechanism independent of its
enzymatic function [PMID 16329111]
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