Molecular Cloning of Human Growth Inhibitory Factor CDNA and Its Down-Regulation in Alzheimer’s Disease

Tsuji, Shoji; Kobayashi, Hisashi; Uchida, Yuzo; Ihara, Yasuo; Miyatake, Tadashi

doi:10.1007/978-1-4757-9145-7_97

Cited by 49 publications

(74 citation statements)

References 42 publications

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“…Although MT-3 was initially reported to be downregulated during AD, this is unfortunately not a consistent finding (40,41,71,76,(132)(133)(134). Whether this has to do with methodological problems (as discussed above, different antibodies give different results) or different AD etiologies is currently unclear.…”

Section: Transgenic Mice Show Different Metallothionein-3 Functionsmentioning

confidence: 97%

“…Initially regarded as a CNS-specific isoform (11, [40][41][42], it is now clear that MT-3 is expressed in other tissues, in some cases in a development-dependent manner (43)(44)(45)(46)(47)(48)(49). In addition to human and mouse brain, MT-3 has been reported in other species such as horse and cow (50), rat (51), pig (52), dog (53), and sheep (54).…”

Section: Expression Of Metallothionein-3 In the Central Nervous Systemmentioning

confidence: 99%

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Metallothioneins and brain injury: What transgenic mice tell us

Hidalgo

2004

Environ Health Prev Med

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In rodents, the metallothionein (MT) family is composed of four members, MT-1 to MT-4. MT-1&2 are expressed in virtually all tissues including those of the Central Nervous System (CNS), while MT-3 (also called Growth Inhibitory Factor) and MT-4 are expressed prominently in the brain and in keratinizing epithelia, respectively. For the understanding of the physiological functions of these proteins in the brain, the use of transgenic mice has provided essential information. Results obtained in MT-1&2-null mice and in MT-1-overexpressing mice strongly suggest that these MT isoforms are important antioxidant, anti-inflammatory and antiapoptotic proteins in the brain. Results in MT-3-null mice show a very different pattern, with no support for MT-1&2-like functions. Rather, MT-3 could be involved in neuronal sprouting and survival. Results obtained in a model of peripheral nervous system injury also suggest that MT-3 could be involved in the control of nerve growth.

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Section: Transgenic Mice Show Different Metallothionein-3 Functionsmentioning

confidence: 97%

Section: Expression Of Metallothionein-3 In the Central Nervous Systemmentioning

confidence: 99%

Metallothioneins and brain injury: What transgenic mice tell us

Hidalgo

2004

Environ Health Prev Med

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“…Measurements of individual MT mRNA levels, however, clearly demonstrate differential expression of specific MT-1 isoforms in human tissues and cell lines (15)(16)(17). The MT-3 (18,19) and mRNAs are expressed in even narrower ranges of cell types.…”

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confidence: 99%

Quantitation of Human Metallothionein Isoforms: A Family of Small, Highly Conserved, Cysteine-rich Proteins

Mehus

Muhonen

Garrett

et al. 2014

Molecular & Cellular Proteomics

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Human metallothioneins (MTs) are important regulators of metal homeostasis and protectors against oxidative damage. Their altered mRNA expression has been correlated with metal toxicity and a variety of cancers. Current immunodetection methods lack the specificity to distinguish all 12 human isoforms. Each, however, can be distinguished by the mass of its acetylated, cysteine-rich, hydrophilic N-terminal tryptic peptides. These properties were exploited to develop a bottom-up MALDI-TOF/TOF-MS-based method for their simultaneous quantitation. Key features included enrichment of N-terminal acetylated peptides by strong cation exchange chromatography, optimization of C18 reversed-phase chromatography, and control of methionine oxidation. Combinations of nine isoforms were identified in seven cell lines and two tissues. Relative quantitation was accomplished by comparing peak intensities of peptides generated from pooled cytosolic proteins alkylated with 14 N-or 15 N-iodoacetamide. Absolute quantitation was achieved using 15 Niodoacetamide-labeled synthetic peptides as internal standards. The method was applied to the cadmium induction of MTs in human kidney HK-2 epithelial cells expressing recombinant MT-3. Seven isoforms were detected with abundances spanning almost 2 orders of magnitude and inductions up to 12-fold. The protein-to-mRNA ratio for MT-1E was one-tenth that of other MTs, suggesting isoform-specific differences in protein expression efficiency. Differential expression of MT-1G1 and MT-1G2 suggested tissue-and cell-specific alternative splicing for the MT-1G isoform. Protein expression of MT isoforms was also evaluated in human breast epithelial cancer cell lines. Estrogen-receptor-positive cell lines expressed only MT-2 and MT-1X, whereas estrogen-receptor-negative cell lines additionally expressed MT-1E. The combined expression of MT isoforms was 38-fold greater in estrogen-receptornegative cell lines than in estrogen-receptor-positive cells. These findings demonstrate that individual human MT isoforms can be accurately quantified in cells and tissues at the protein level, complementing and expanding mRNA measurement as a means for evaluating MTs as potential biomarkers for cancers or heavy metal toxicity. Molecular & Cellular

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“…the recent discovery of the brain-specific MT-III, which inhibits neuron survival in vitro, the implications of MTs in the brain pathophysiology are strengthened [29]. MT-III mRNA may or may not be down regulated in patients with Alzheimer's disease (AD) [5,29].…”

mentioning

confidence: 99%

“…MT-III mRNA may or may not be down regulated in patients with Alzheimer's disease (AD) [5,29]. There is also a controversy as to the localization of MT-III in the brain.…”

mentioning

confidence: 99%

Localization of Metallothioneins-I & -II and -III in the Brain of Aged Dog.

Kojima

Shimada

Morita

et al. 1999

The Journal of Veterinary Medical Science

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ABSTRACT. Localization of metallothionein (MT) -I & -II and MT-III and its significance in the brain aging in dogs were examined using immunohistological and molecular pathological techniques. MT-I & -II immunohistochemistry showed positive staining in the hypertrophic astrocytes throughout the aged dog brains; these MT-I & -II immunoreactive astrocytes were predominant in the cerebral cortex and around the blood vessels in the brain. These findings dominated in the brain regions with severe age-related morphological changes. In situ hybridization using MT-I mRNA riboprobes also demonstrated signals for MT-I mRNA in these hypertrophic astrocytes. Immunohistochemistry using a guinea pig antiserum against a synthetic polypeptide of canine MT-III demonstrated positive MT-III immunoreactivity predominantly in neurons in the Zn-rich regions such as hippocampus and parahippocampus. The findings were supported by in situ hybridization using MT-III mRNA riboprobes. Both MT-III immunoreactivity and signals for MT-III mRNA were demonstrated in neurons in the brain regardless of the intensity of the age-related changes. These results suggest, first, MT-I & -II may be induced in relation to the progress of the age-related morphological changes in the brain, playing an important role in the protection of the brain tissue from the toxic insults responsible for the brain aging, and second, MT-III may play a role in maintenance of Zn-related essential functions of the brain.-KEY WORDS: aging, brain, canine, in situ hybridization, metallothionein.

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Molecular Cloning of Human Growth Inhibitory Factor CDNA and Its Down-Regulation in Alzheimer’s Disease

Cited by 49 publications

References 42 publications

Metallothioneins and brain injury: What transgenic mice tell us

Metallothioneins and brain injury: What transgenic mice tell us

Quantitation of Human Metallothionein Isoforms: A Family of Small, Highly Conserved, Cysteine-rich Proteins

Localization of Metallothioneins-I & -II and -III in the Brain of Aged Dog.

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