Polymorphism in the major histocompatibility complex class II genes of Peromyscus leucopus.
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M D Crew
Publications and source records attributed to M D Crew.
Thyroid hormone transcriptional regulatory region of the growth hormone gene.
By deletion-transfection analysis, a region of the rat growth hormone gene has been identified which directs accurate, thyroid hormone responsive transcriptional initiation in vivo. In addition, a thyroid hormone-responsive DNase I hypersensitive domain containing three discrete hypersensitive sites has been identified near the GH promoter. One site is coincident with the TATA homology, and the others lie approximately 150 nucleotides 5' and 3' of this sequence. The TATA and 5' flanking DNA hypersensitive sites are located in the region of the gene which promotes hormone-responsive gene transcription. Based on these results, it is possible that the molecular basis for thyroid hormone induction of GH gene transcription includes binding of the occupied receptor to chromatin sites flanking the TATA homology, promoting binding of the TATA activating protein to this sequence. Together, these events may enhance the rate of RNA polymerase II initiation at the promoter.
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Sequences essential for activity of the thyroid hormone responsive transcription stimulatory element of the rat growth hormone gene.
Thyroid hormone dependent transcription stimulatory and inhibitory elements exist at the 5'-end of the rat GH (rGH) gene (TSE and TIE, respectively). In this study, the location of the sequences essential for TSE activity was examined using stably transfected GC cells. Because the TIE may influence TSE activity, we investigated TSE activity both on the rGH promoter, in the presence of the TIE, and on the viral thymidine kinase promoter, with the TIE deleted. The results of these studies indicate that the minimum sequences essential for TSE activity exist between positions -194 and -169 of the rGH gene.
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Discrete positive and negative thyroid hormone-responsive transcription regulatory elements of the rat growth hormone gene.
We have recently shown that a thyroid hormone-responsive transcription stimulatory element exists in the 5'-flanking DNA near the rat growth hormone (rGH) gene (Crew, M. D., and Spindler, S. R. (1986) J. Biol. Chem. 261, 5018-5022). Progressive deletion-transfection analysis of the 5' end of the gene has led to the identification of two genetic elements responsive to thyroid hormone. The first of these is a thyroid hormone-responsive transcription stimulatory element, or TSE. The TSE induced a thyroid hormone-dependent induction-attenuation transcription cycle similar to that of the natural rGH gene. Deletion of sequences between positions -254 and -241 in the rGH 5'-flanking DNA eliminated TSE activity. The second regulatory element is a thyroid hormone-responsive transcription inhibitory element (TIE). When this element was active, thyroid hormone strongly but transiently inhibited rGH promoter utilization. Deletion of sequences between nucleotides -46 and -21 abolished the effects of the TIE. To determine whether the TSE and TIE are enhancer-like, we ligated various regions of rat growth hormone 5'-flanking DNA containing these elements to a chimeric test gene containing the Herpes simplex virus thymidine kinase promoter. Thyroid hormone activated heterologous promoter utilization when a rat growth hormone 5'-flanking DNA fragment containing the TSE (-520 to -115) was linked in cis, regardless of the distance or orientation of the TSE with respect to the promoter. These data suggest that the TSE is a thyroid hormone-dependent enhancer. In contrast, when the TIE was placed immediately 5' to the thymidine kinase promoter, transcription was not effected by 3,5,3'-L-triiodothyronine, suggesting that the TIE is not enhancer-like.
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Age-related decrease of growth hormone and prolactin gene expression in the mouse pituitary.
The effects of aging on pituitary GH, PRL, and alpha-tubulin messenger RNA (mRNA) levels were measured in 3-, 12-, and 27-month-old male C57BL/6J mice by dot-blot hybridization. The amount of GH and PRL mRNA in the pituitary deceased dramatically with age. However, total poly(A+) RNA (mRNA), as measured by hybridization with radioactively labeled oligo-(dT), was not altered during aging. In addition, there were no age-related changes in the level of alpha-tubulin mRNA. Thus, the effects of aging on GH and PRL mRNA levels are specific; the levels of the majority of cellular mRNAs are not altered with age. GH and mRNA levels decreased 35% between 3 and 12 months (P less than 0.05) and a total of 75% after 27 months (P less than 0.01). PRL mRNA levels decreased 65% between 12 and 27 months (P less than 0.01), although there was no significant decrease before 12 months. Whereas T3 is the most potent regulator of GH gene expression, we did not detect any significant age-related change in serum T3 levels. These results suggest that factors other than T3 play a role in the age-related decline in GH and PRL gene expression.
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Thyroid hormone regulation of the transfected rat growth hormone promoter.
A region of the rat growth hormone gene and 5' flanking DNA has been identified which promotes accurate, thyroid hormone-regulated transcriptional initiation. GC rat pituitary tumor cells were transfected with chimaeric plasmids containing various lengths of rat growth hormone gene and 5' flanking DNA fused to the coding region of the dominant selectable marker gene neo. Thyroid hormone induction of rGH-neo RNA was observed by Northern and dot blot analysis of cells transfected with rGH-neo chimaeric genes sharing the rat growth hormone gene and upstream regions from -235 to +11. Initiation of rGH-neo transcription was mapped by S1 nuclease protection to the in vivo initiation site of the natural growth hormone gene. Transcription of the most deleted thyroid hormone responsive construct involved an induction-attenuation cycle qualitatively similar to the response of the natural gene. However, the 3,5,3'-triiodo-L-thyronine responsiveness of this deleted construct was approximately 2- to 3-fold less than that of less deleted rGH-neo genes tested. These results suggest that, at a minimum, the sequences required for the cyclic 3,5,3'-triiodo-L-thyronine transcriptional response are located within the region of the gene from -235 to +11. Other sequences essential for full responsiveness appear to be located elsewhere in the 5'-flanking DNA. Rat growth hormone promoter utilization appears to be strongly cell-type dependent. We obtained stable transfectants with rGH-neo constructs only in GC cells.
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