Human metallothionein genes are clustered on chromosome 16.

Karin, Michael; Eddy, Roger L.; Henry, Willie; Haley, L.L.; Byers, Mary G.; Shows, T.B.

doi:10.1073/pnas.81.17.5494

Cited by 93 publications

(47 citation statements)

References 26 publications

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“…Increased repair in an amplified CHO MT-I gene after induction with a heavy metal has also been observed recently (23). Induction of the MT genes by heavy metals and glucocorticoids is regulated primarily at the level of transcription initiation, although there is a small effect of glucocorticoid induction on MT mRNA stability (6,8 (12,14,33). A more compact chromatin structure may also be associated with regions surrounding developmentally regulated genes, such as hMT-IB, when they are in a highly methylated, nonexpressed state and with regions surrounding nonexpressed, processed pseudogenes, such as hMT-IIB.…”

Section: Discussionmentioning

confidence: 78%

“…A full-length cDNA clone of human hMT-II mRNA, phMT-I13 (provided by M. Karin, University of California at San Diego), was used to detect the hMT genes in human genomic DNA. A BamHI-PvuII fragment of phMT-113, which contains the hMT-II coding region, was used to detect hMT mRNA, a PvuII-PvuI fragment of phMT-113, containing the 3' untranslated region of this cDNA, was used to detect specifically the hMT-IIA mRNA (8), and an EcoRI fragment of pLS2 (obtained from J. Sylvester, University of Pennsylvania, Philadelphia), which contains most of a human 18S ribosomal gene, was used to detect 18S rRNA. …”

Section: Methodsmentioning

confidence: 99%

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Differential repair of DNA damage in the human metallothionein gene family.

Leadon

Snowden

1988

Mol. Cell. Biol.

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We studied the repair of UV-and aflatoxin B1 (AFB,)-induced damage in the human metallothionein (hMT) gene family. After exposure to either UV or AFB1, DNA damage was initially repaired faster in the DNA fragments containing the transcribed hMT-IA, hMT-IE, and hMT-IIA genes than in the genome overall. By 6 h posttreatment, there was at least twice as much repair in these genes as in the rest of the genome. Repair of UV damage in the hMT-IB gene, which shows cell-type specific expression, and in the hMT-IIB gene, which is a nontranscribed processed pseudogene, was about the same as in the rest of the genome, whereas repair of AFB1-induced damage was deficient in these two genes. Inducing transcription of the three expressed hMT genes with CdCl2 or of only the hMT-UA gene with dexamethasone increased the initial rate of repair in the induced genes another twofold over the rate observed when they were transcribed at a basal level. The rates of repair in the hMT-IB and hMT-UB genes were not altered by these inducing treatments. Transcription of the hMT genes was transiently inhibited after UV irradiation. Inducing transcription of the genes did not shorten this UV-induced delay. Thus, the efficiency of repair of damage in a DNA sequence is dependent on the level of transcriptional activity associated with that sequence. However, an increased efficiency in repair of a gene itself is not necessarily coupled to recovery of its transcription after DNA damage.An increasingly important area of investigation of DNA damage and excision repair is whether all sequences in the eucaryotic genome are repaired with the same efficiency. Evidence has been presented for a more rapid removal of pyrimidine dimers from the highly amplified dihydrofolate reductase (DHFR) gene both in Chinese hamster ovary cells (2, 3) and in human cells (20), for preferential repair of UV damage in the expressed c-abl gene but not the inactive c-mos locus in mouse cells (17), and for more efficient repair of UV and aflatoxin B1 (AFB1)-induced damage in an active and integrated pSV2-gpt than in the bulk of the monkey genome (12). Recent evidence indicates that the removal of UV damage from both the hamster and the human DHFR gene is more rapid in the transcribed strand of the gene than in the nontranscribed strand (21). The major distinction between rodent and primate cells in repair of UV damage in transcriptionally active DNA appears to be one of restricted repair versus the rate of repair. Rodent cells appear to restrict repair of UV damage to actively transcribed sequences, possibly leaving the remainder of the genome relatively excluded from the repair process. In primate cells, preferential repair is observed as a more rapid rate of repair in active DNA sequences.In this study, we examined the repair of UV and AFB1 damage in the nonamplified human metallothionein (hMT) gene family by using an immunological method that isolates DNA fragments containing bromouracil (BrUra) in repair patches by means of a monoclonal antibody that recognizes BrUra (...

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Section: Discussionmentioning

confidence: 78%

Section: Methodsmentioning

confidence: 99%

Differential repair of DNA damage in the human metallothionein gene family.

Leadon

Snowden

1988

Mol. Cell. Biol.

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“…MT exists in different isoforms and most human MT genes, including the mainly functional ones (MT IA and MT IIA), are localized on chromosome 16 (Karin et al, 1984;Le Beau et al, 1985), and MT IIA is the major human MT gene, accounting for 50% of the MT mRNA expression. Then, to screen MT-positive cases, we used common oligonucleotide sequences shared among MT genes (93-98% homology) as a general MT probe set.…”

Section: Oligo-dnasmentioning

confidence: 99%

Metallothionein expression correlates with metastatic and proliferative potential in squamous cell carcinoma of the oesophagus

et al. 1999

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Squamous cell carcinoma (SCC) of the oesophagus is well recognized for its aggressive biological behaviour, in respect of local infiltration and metastases to regional lymph nodes and distant organs (Orrigner, 1997). Extra-oesophageal tumour spread is present in 70% of cases at the time of diagnosis, and the 5-year survival is only 3% when lymph node metastases are present, compared with 42% in lymph node negative patients (Orrigner, 1997). Patients with distant metastasis also have a poor prognosis, with a 5-year survival rate of 5% or less (Mandard et al, 1984;Orrigner, 1997).Metastasis is a multistep process involving complex associations of tumour cells with host cells or with matrix (Stracke and Liotta, 1995). Recently, genetic mechanisms underlying metastasis and pathogenesis of oesophageal SCC have been explored in several studies: int-2/hst-1 co-amplification correlated with high incidence of metastasis in distant organs (Kitagawa et al, 1991), loss of heterozygosity of the DCC gene associated with the degree of lymph node metastasis (Miyake et al, 1994), and mutation of the p53 gene in the pathogenesis (Hollstein et al, 1990;Meltzer et al, 1991) of SCC. However, there are only a limited number of reports on the prognostic indicators for invasion and metastasis of oesophageal SCC.Metallothioneins (MTs) have been described in most vertebrate and invertebrate species as low molecular weight proteins. Overexpression of MT was described in a variety of human tumours, in relation to different stages of tumour development and progression (Jasani and Schmid, 1997). MT was considered as a potential prognostic marker in invasive ductal carcinoma of the breast by Schmid et al (1993) and others (Fresno et al, 1993;Goulding et al, 1995, Oyama et al, 1996. In skin carcinoma (Zelger et al, 1994), melanoma (Zelger et al, 1993), cervical carcinoma (Lim et al, 1996) and pancreatic carcinoma (Ohshio et al, 1996), MT overexpression appears to be predominantly associated with more advanced, highly malingant tumours. To the contrary, Öfner et al (1994) reported that MT overexpression in colorectal carcinoma was associated with better clinical outcome and tumour stages. Therefore, MT overexpression may be paradoxically associated in some tumours with better clinical outcome.Tumour MT level also has been reported to correlate with resistance to anticancer reagents (Kelley et al, 1988;Kasahara et al, 1991;Chin et al, 1993;Kondo et al, 1995;Hishikawa et al, 1997). In oesophageal SCC, we already reported that MT protein expression might be a significant determinant of prognosis, in particular, associated with cisplatin resistance (Hishikawa et al, 1997). Patients with MT protein-negative tumours survived longer when treated with cisplatin than those with MT protein-positive tumours. However, the exact biological significance of the expression of MT protein and mRNA is largely unknown in the clinical setting of oesophageal SCC.Therefore, in the present study, we have investigated the expressions of both MT mRNA and its protein in...

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“…The human MT (hMT) family consists of at least 12 genes, of which the functional members are located on chromosome 16 (19). There are at least seven functional genes (22,32; unpublished data) and two mutant MT sequences clustered at 16q22 (27).…”

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confidence: 99%

Structure and tissue-specific expression of the human metallothionein IB gene.

Heguy¹,

West²,

Richards³

et al. 1986

Mol. Cell. Biol.

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The human metallothionein (MT) IB gene (hMT-IB) is located in a region of human DNA containing at least four tandemly arranged MT genes. As deduced from its sequence, hMT-I] is likely to encode a functional protein. However, the predicted amino acid sequence differed from the hMT-I amino acid sequence in four positions. Most remarkable was the presence of an additional cysteine. Like other MT genes, hMT-IB has at least two copies of the metal-responsive element upstream from the transcription initiation site. These elements probably are responsible for the metal responsiveness of the hMT-IB promoter, leading to inducible expression of fused heterologous genes. Unlike the hMT-IIA and hMT-IA genes described previously, which are expressed in many different cell types, a high level of expression of the endogenous hMT-In gene could be detected only in human hepatoma and renal carcinoma cell lines. Therefore, this is the first MT gene described which exhibits tissue specificity of expression. This specificity is controlled by a cis-acting mechanism involving methylation, since incubation of nonexpressing cells with an inhibitor of DNA methylation led to activation of the hMT-IB gene. In support of this notion, we found that the 5' flanking region of the hMT-IB gene was highly methylated in HeLa cells, a nonexpressing cell type, but it was not methylated in a hepatoma (expressing) cell line.

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Human metallothionein genes are clustered on chromosome 16.

Cited by 93 publications

References 26 publications

Differential repair of DNA damage in the human metallothionein gene family.

Differential repair of DNA damage in the human metallothionein gene family.

Metallothionein expression correlates with metastatic and proliferative potential in squamous cell carcinoma of the oesophagus

Structure and tissue-specific expression of the human metallothionein IB gene.

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