Regulation of expression of liver‐specific enzymes

Kielty, Cay M.; Povey, S.; Hopkinson, D. A.

doi:10.1111/j.1469-1809.1982.tb01582.x

Cited by 77 publications

(7 citation statements)

References 21 publications

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“…The human TG gene has been localized to the same chromosome band as MYC, 8q24. Further, the human homolog of Gpt-1 also has been assigned provisionally to 8q (21,22). The present finding of close linkage between the murine Tgn and Gpt-J genes lends support to this assignment.…”

Section: Resultssupporting

confidence: 70%

The congenital goiter mutation is linked to the thyroglobulin gene in the mouse.

Taylor¹,

Rowe²

1987

Proc. Natl. Acad. Sci. U.S.A.

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Rat thyroglobulin (TG) cDNA clones were used to identify DNA restriction fragment variants among inbred mouse strains. One of these variants was shown to be closely linked to the recessive mutation congenital goiter (cog), which had previously been mapped to mouse chromosome 15. These results indicate that the structural gene for thyroglobulin is on chromosome 15 and suggest that a mutation at the site of the TG gene is the basis of the cog defect. No differences were observed between cog/cog and +/+ DNA in Southern blots using TG cDNA probes corresponding to 88% of the coding sequences, suggesting that the cog mutation is not due to a large deletion of this portion of the gene. Neither was there any obvious qualitative or quantitative difference between mutant and normal TG mRNA as judged by blot hybridization of electrophoretically fractionated thyroid RNAs. The thyroglobulin gene locus (Tgn) was mapped near the glutamic-pyruvic transaminase isoenzyme locus Gpt-1. The Tgn locus is syntenic with the c-myc protooncogene locus (Myc) in the mouse as in the rat and man.The thyroid hormones thyroxine (T4) and triiodothyronine (T3) are synthesized in a complex process from the Mr 660,000 thyroglobulin (TG) protein precursor (1). TG is a large glycoprotein consisting of two identical subunits whose primary polypeptide chain is of Mr 300,000. Two pairs of primary hormonogenic tyrosine residues have been identified near the amino and carboxyl termini ofthe polypeptide (2, 3). These tyrosine residues are iodinated and coupled by ether bonds. Thyroid hormones are released when TG is endocytosed by the thyrofollicular cells from the follicular lumen, where it is stored, and degraded in the lyzosomes by proteolytic digestion. Parts of the TG gene have been cloned in several species including the cow, goat, rat, and man (3-7). The rat TG gene consists of42 exons, spanning more than 170 kilobases (kb), and is transcribed into an -8500-nucleotide mRNA (5). The human TG gene is >300 kb long (6). Hereditary hypothyroidism due to disorders of TG biosynthesis has been described in both man and several species of domestic animals (1,4,8). Recently, a mouse mutation, congenital goiter (cog), was described that in homozygous condition causes primary hypothyroidism with goiter (9). We have used rat TG cDNA clones to identify and map DNA restriction fragment variants associated with the mouse TG gene. We show that the cog mutation is closely linked to these TG restriction fragment variants and is therefore probably a mutation in the mouse TG gene.

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Section: Resultssupporting

confidence: 70%

The congenital goiter mutation is linked to the thyroglobulin gene in the mouse.

Taylor¹,

Rowe²

1987

Proc. Natl. Acad. Sci. U.S.A.

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“…FHA7 and FGIOE8 derive from the fusion of Faza 967 with FH or G cells, respectively. Their selection in HAT medium has been described previously (Kielty et al, 1982b). FG10E8B is a subclone of FG10E8 isolated in 6-thioguanine; as expected, these cells have lost the human X chromosome.…”

mentioning

confidence: 78%

HNF4 and HNF1 as well as a panel of hepatic functions are extinguished and reexpressed in parallel in chromosomally reduced rat hepatoma-human fibroblast hybrids.

Hamon-Benais

Angrand

et al. 1993

The Journal of Cell Biology

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Abstract. Rat hepatoma-human fibroblast hybrids of two independent lineages containing only 8-11 human chromosomes show pleiotropic extinction of thirteen out of fifteen hepatic functions examined. Reexpression of the entire group of functions most often occurs in a block, and except for one discordant subclone, correlates with loss of human chromosome 2. The extinguished cells and their reexpressing derivatives have been examined for the expression of seven liverenriched transcription factors. C/EBP' LAP, DBP, HNF3, and vHNF1 expression are not systematically extinguished in parallel with the hepatic functions. However, HNFI and HNF4 show a perfect correlation with phenotype: these factors are expressed only in the cells showing pleiotropic reexpression. Since recent evidence indicates that HNF4 controls HNF1 expression, it can be proposed that the HNF4 gene is the primary target of the pleiotropic extinguisher.

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“…References to many of the loci mapped in man can be found in refs. 1-4 and 9; references for the remaining loci are the following: Adk (16), Afp (17), Asl (18), C-3 (19), C-4 (20,21), Cs (22), Dia-i (23), , Fpgs (25), Gdc-i (26), Got-2 (27), Ifrc (28,29), Lipa (30), Lv (31), Prgs (32), Sdh-i (33), Upg-i (34), and Ups (35 ments occur more frequently than others, it is doubtful that such nonrandomness would materially affect the overall distribution of conserved segment lengths. If, however, rearrangements are not permitted in large chromosomal regions, then deviations from a random distribution of conserved segment lengths should be evident.…”

mentioning

confidence: 99%

Lengths of chromosomal segments conserved since divergence of man and mouse.

Nadeau¹,

Taylor²

1984

Proc. Natl. Acad. Sci. U.S.A.

539

322

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Linkage relationships of homologous loci in man and mouse were used to estimate the mean length of autosomal segments conserved during evolution. Comparison of the locations of >83 homologous loci revealed 13 conserved segments. Map distances between the outermost markers of these 13 segments are known for the mouse and range from 1 to 24 centimorgans. Methods were developed for using this sample of conserved segments to estimate the mean length of all conserved autosomal segments in the genome. This mean length was estimated to be 8.1 ± 1.6 centimorgans. Evidence is presented suggesting that chromosomal rearrangements that determine the lengths of these segments are randomly distributed within the genome. The estimated mean length of conserved segments was used to predict the probability that certain loci, such as peptidase-3 and renin, are linked in man given that homologous loci are x centimorgans apart in the mouse. The mean length of conserved segments was also used to estimate the number of chromosomal rearrangements that have disrupted linkage since divergence of man and mouse. This estimate was shown to be 178 ± 39 rearrangements.Recent progress in mammalian genetics has permitted the chromosomal assignment of numerous biochemically defined loci and the development of linkage maps for a variety of species (1)(2)(3)(4). Analysis of these linkage maps provides a useful means for studying genomic organization and evolution. For example, linkage of homologous loci on the X chromosome has been rigorously conserved in mammals, suggesting that chromosomal rearrangements involving the X chromosome and autosomes have been rejected by natural selection (5, 6). By contrast, analyses of conserved and disrupted autosomal linkages show that closely linked loci in one species tend to be linked in other species and loci that are loosely linked in one species tend to be unlinked in other species (7). It is not known, however, whether conserved segments are protected from chromosome rearrangement and may therefore represent adaptive combinations of loci or whether conserved segments reflect a random distribution of chromosomal rearrangements within the genome.Linkage maps for man and mouse are now sufficiently complete to warrant more quantitative analyses of the extent of linkage conservation and evaluation of a number of arguments concerning genomic organization and evolution. Perhaps the most useful parameter in these analyses is the length of conserved segments. There are two problems in calculating the lengths of these segments, however. The first is that the lengths of identified conserved segments are not precisely known because the lengths are probably greater than the distance between the outermost markers defining the segments. The second problem is that such lengths are based on segments marked by two or more homologous markers; segments lacking identified markers and segments with a single identified marker are necessarily excluded from these analyses. Because large segments are more likely to contain ...

show abstract

Regulation of expression of liver‐specific enzymes

Cited by 77 publications

References 21 publications

The congenital goiter mutation is linked to the thyroglobulin gene in the mouse.

The congenital goiter mutation is linked to the thyroglobulin gene in the mouse.

HNF4 and HNF1 as well as a panel of hepatic functions are extinguished and reexpressed in parallel in chromosomally reduced rat hepatoma-human fibroblast hybrids.

Lengths of chromosomal segments conserved since divergence of man and mouse.

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