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Thyroid Hormone-Induced Expression of Specific Somatostatin Receptor Subtypes Correlates with Involution of the TtT-97 Murine Thyrotrope Tumor¹

Department of Medicine, Division of Endocrinology, University of Colorado Health Science Center (R.A.J., V.D.S., J.M.D., D.F.G., W.M.W., E.C.R.), Denver, Colorado 80262; Sandoz Pharma (C.B., F.R.), Basel, Switzerland; and the Department of Medicine, Division of Endocrinology, University, of Newcastle-upon-Tyne (R.A.J.), Newcastle-upon-Tyne, United Kingdom

Address all correspondence and requests for reprints to: Dr. William M. Wood, Department of Medicine, Division of Endocrinology, Campus Box B151, University of Colorado Health Science Center, 4200 East Ninth Avenue, Denver, Colorado 80262. E-mail: Andy.James{at}btinternet.com

	Abstract

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Following the protracted hypothyroid state, treatment with thyroid hormone will induce a decline in TSH and reduce thyrotrope hyperplasia. Somatostatin is a hypothalamic peptide that has been implicated in the negative regulation of TSH secretion in the thyrotrope. Moreover, analogs of native somatostatin have potent TSH-reducing and growth-retarding effects on human thyrotropinomas. The TtT-97 tumor is an in vivo murine thyrotropic model that has retained its physiological response to thyroid hormone. This study investigates the regulation of somatostatin receptor subtypes in this tumor. TtT-97 tumors, actively growing in hypothyroid mice, did not express any significant somatostatin receptor messenger RNA (mRNA) or protein. T₄ administration resulted in a reduction in TSHß mRNA expression and a marked degree of tumor involution. Analysis of residual tumors from thyroid hormone-treated mice showed the specific up-regulation of SSTR1 and SSTR5 mRNA subtypes and the appearance of abundant, high affinity SSTR receptor-binding sites within the tumor. Thus, the TtT-97 tumor provides a thyrotrope-specific model in which to study the regulation of somatostatin receptor subtypes by thyroid hormone and correlate this expression with both antisecretory and antiproliferative effects.

	Introduction

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THE TtT-97 MOUSE pituitary thyrotrope cell line is a well differentiated tumor that synthesizes and secretes TSH (1). The tumor is propagated by sc interscapular injection of dispersed TtT-97 tumor tissue into radiothyroidectomized mice. The implanted TtT-97 tumor progressively enlarges and secretes increasing amounts of intact TSH. If mice with established tumors are supplemented with T₄, there is a reduction of TSH secretion (2) and a gradual involution of the tumor (3). Both effects are reversible upon withdrawal of T₄. This phenomenon indicates a retention of differentiated function and an intact negative feedback regulation by thyroid hormone on both growth and secretion of the TtT-97 tumor. As such, this murine tumor model can be used to study the mechanism underlying physiological regulation of the thyrotrope by thyroid hormone. In vitro studies using TtT-97 explants have confirmed that T₃ has a direct effect on intact TSH production (4) and on TSHß and -subunit steady state messenger RNA (mRNA) at the level of transcription (5).

In humans as well as in mice, the protracted hypothyroid state is known to induce high levels of TSH secretion and pituitary enlargement due to hyperplasia of thyrotrope cells caused by the lack of negative feedback regulation by thyroid hormone (6). Treatment of hypothyroid patients with thyroid hormone not only corrects the symptoms of hypothyroidism, but also reverses the pituitary enlargement. The mechanism underlying the antiproliferative effect of thyroid hormone is unknown. However, the hypothalamic factor somatostatin decreases pituitary TSH secretion, and long acting analogs of somatostatin have been shown to not only decrease TSH secretion, but also cause tumor shrinkage when used to treat human pituitary thyrotropinomas (7, 8, 9). In fact, previous in vitro studies have shown that thyroid hormone and somatostatin acted synergistically to control TSH secretion. The cooperative effect of thyroid hormone and somatostatin was consistent with a thyroid hormone-induced increase in cell surface somatostatin receptors (10). To date, five specific subtypes of the somatostatin receptor, SSTR1-5,² have been cloned, each of which has a characteristic, tissue-specific, pattern of expression (11). There is a high degree of homology between species for a given receptor subtype, suggesting a conservation of function. Expression of SSTR2 is highly correlated with the suppression of GH release from pituitary somatotrophs in both normal pituitary and rat pituitary tumor cell lines (12). Furthermore, SSTR2-specific analogs have been shown to have a controlling influence on the cell cycle, thereby exerting a potential antiproliferative effect (13). The contributions of other somatostatin receptor subtypes to the control of proliferation and secretion in other normal and neoplastic endocrine tissues are largely unknown. The aim of this study was to identify which somatostatin receptor subtypes are expressed in TtT-97 murine thyrotropic tumors and determine how they may be influenced by thyroid hormone, thus mediating decreases in TSH secretion and tumor size.

	Materials and Methods

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Experimental design
The experimental protocol used for these studies has been previously described (3). Briefly, LAF₁ mice were radiothyroidectomized (150 µCi Na¹³¹I/mouse) 8 weeks before the injection of homogenized TtT-97 thyrotropic tumor, which was obtained from a single donor animal (2). After 12–18 weeks, 18 hypothyroid mice with tumors of equal size were divided into 3 groups of 6 mice each. The mice from 1 group were killed (baseline); the remaining 12 mice entered a 4-week treatment period in which 6 mice received thyroid hormone supplementation (5 mg/liter T₄) in their drinking water (treatment), whereas the remaining 6 mice were maintained unsupplemented in the hypothyroid state (controls). After the experimental period, the mice were anesthetized and killed, and their tumors were removed. Tumor volumes and weights were recorded, and blood samples were taken for measurement of thyroid hormone content by RIA (14). Four randomly selected tumors from each group (baseline/control and treated) were excised, rapidly homogenized in 10 vol of a 4 M guanidinium isothiocyanate solution supplemented with 5% (vol/vol) mercaptoethanol, and stored at -20 C. RNA was isolated by sedimentation through 5.7 M cesium chloride, and polyadenylated RNA was purified on oligo(deoxythymidine)-cellulose (15).

Northern blot analysis
Radiolabeled probes corresponding to the coding regions of each somatostatin receptor subtype were prepared by nick translation (Life Technologies, Gaithersburg, MD) using [-³²P]deoxy-CTP. The complementary DNAs (cDNAs) encoding mouse SSTR1, SSTR2, and SSTR3 were donated by Dr. Graeme Bell (University of Chicago, Chicago, IL). Rat SSTR4 and SSTR5 cDNAs were provided by Dr. Michael Berelowitz (State University of New York, Stony Brook, NY). The sequence for mouse SSTR4 has recently become available (GenBank accession no. U26176) and displays 93.8% homology to rat SSTR4; mouse SSTR5 has yet to be cloned. Further comparison of the mouse/rat protein shows 98% homology for SSTR1 and SSTR2 receptors and 93% homology for SSTR3, respectively, indicating a high degree of conservation of amino acid sequence between individual subtypes from closely related rodent species (12).

Initial Northern blot analysis was performed, using total RNA from hypothyroid tumors. Subsequent Northern blots were performed on two representative tumors from each group using 10 µg polyadenylated [poly(A)⁺] mRNA/lane separated on a 6% formaldehyde-1% agarose gel with [-³²P]deoxy-CTP-labeled HindIII DNA fragments as size standards. After adequate separation of mRNA, the gel was washed in distilled water, then blotted onto a 0.2-µm pore nylon membrane (Nytran, maximum strength, Schleicher and Schuell, Keene, NH) using downward transfer (Turboblot, Schleicher and Schuell). After overnight transfer, the nylon membrane was subjected to optimal UV cross-linking (FB-UVXL-1000, Fisher Scientific, Pittsburgh, PA). Nylon membranes were prehybridized for 2–4 h at 42 C with a prehybridization mix containing sodium pyrophosphate buffer (1 M NaCl, 10 mM sodium phosphate, and 0.1% sodium pyrophosphate), 1% SDS, salmon sperm DNA (0.25 mg/ml), 5 x Denhardt’s solution (0.1% each Ficoll, polyvinylpyrrolidone, and BSA), and 50% formamide. Radiolabeled probes were extracted with phenol-chloroform and purified by centrifugation through a Sephadex G-50 column. For each probe, 70–80 x 10⁶ counts were boiled for 5 min with deproteinized salmon sperm DNA (100 µl of 10 µg/µl) before addition to the nylon membranes. Hybridization was carried out at 42 C overnight. Posthybridization washes were performed with appropriate dilutions of 20 x SSC buffer (3 M sodium chloride and 0.3 M sodium citrate) as follows: 2 x SSC (standard saline citrate) and 0.1% SDS (four washes, 5 min each, 42 C), followed by 0.2 x SSC and 0.1% SDS (once, 20 min, 55 C). Nylon membranes were allowed to air dry for 15 min before being exposed to Kodak Biomax-MR film (Eastman Kodak, Rochester, NY) at -70 C for up to 1 week. A single nylon membrane containing the poly(A)⁺ mRNA extracted from two tumors derived from each group (baseline, control, and thyroid hormone treated) was first probed with mouse (m) SSTR1, then reprobed with rat (r) SSTR5. Preliminary Northern blots showed no cross-reactivity of the mSSTR1-3 or rSSTR4 and rSSTR5 probes, indicating high specificity of each probe for its designate receptor subtype mRNA. After removal of SSTR probes with 0.1 x SSC and 0.5% SDS, (three washes, 20 min each, 65 C), a probe corresponding to the coding region for mouse TSHß was similarly labeled and hybridized. This was followed by a mouse ß-actin probe to confirm equal loading of RNA samples.

Reverse transcription-PCR (RT-PCR) analysis
RT-PCR analyses were carried out by reverse transcription (Superscript II, Life Technologies) of RQ1 deoxyribonuclease (Promega, Madison, WI)-treated TtT-97 total RNA, as previously described (16). Somatostatin receptor subtype-specific PCR was performed for 40 cycles using primer pairs specific for SSTR1-5, respectively. Primers for SSTR1 and SSTR2 were previously described (16). For SSTR4, the primers HS48 (5'-ACCAACATCTACCTGCTCAACCTGG-3') and HS49 (5'-GCATAGTAGTCCAGGGGCTC-3') were used. For SSTR3, the mouse-specific primers MS37 (5'-TTCTCAGGAGTGCCCCGGGGCATG-3') and MS38 (5'-CGATGTTGAGCAGATAGAAAGGCATCCA-3') were used, and for SSTR5, the rodent-specific primers RS51 (5'-GTATTAGTGCCTGTGCTCTACCTGTTGG-3') and RS52 (5'-ACACAGACGTGTAGGTGATGAAGGCTGC-3') were used. Positive controls for each PCR analysis were obtained using cloned human or rodent SSTR1-5 cDNAs, respectively, and mouse genomic DNA. The other cloned human or rodent SSTR cDNA subtypes and a template minus (water) control served as negative controls to ensure specific amplification. Comparison was made to standard RT-PCR coamplification reactions using ß-actin-specific primers to demonstrate mRNA integrity and to relatively quantify the derived products (16).

Receptor autoradiography
Autoradiographic detection of somatostatin receptor protein was carried out as described previously (17) on Cryostat sections of snap-frozen TtT-97 tumor tissue. Briefly, tissue sections were mounted on gelatin-coated glass slides and incubated at room temperature for 2 h in Tris-Cl buffer (pH 7.4) containing 1% BSA, bacitracin (40 µg/ml), and MgCl₂ (5 mM). The somatostatin ligand concentration (¹²⁵I-labeled [Tyr³]SMS 201–995 or ¹²⁵I-labeled [Leu⁸,D-Trp²²,Tyr²⁵]SRIF-28) ranged from 10–30 pM. Nonspecific binding was determined on adjacent slides by coincubation with an excess of either unlabeled SMS 201–995 or SRIF-28 (1 µM). Autoradiograms were obtained by exposing the labeled sections to Hyperfilm ßmax (Amersham, Arlington Heights, IL) at 4 C for 12–16 days.

Animal treatment
Animal studies using LAF1 mice were conducted in a humane manner and were in accordance with the NIH Guide for the Care and Use of Laboratory Animals. The protocols were approved by the committee on animal care and use of the University of Colorado Health Sciences Center (Denver, CO).

	Results

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Baseline mRNA and protein expression
Somatostatin receptor subtype 1–5 mRNAs were not detectable in hypothyroid tumor samples when analyzed by total RNA Northern hybridization (data not shown). Using more sensitive RT-PCR analysis, faint bands (-/+) representing SSTR2 and SSTR4 transcripts were seen in only one of the four tumors analyzed (Table 1). Autoradiography for somatostatin receptor protein by radiolabeled ligand binding was similarly negative in tumors derived from hypothyroid mice (Fig. 1).

View larger version (72K): [in this window] [in a new window]   Figure 1. Autoradiography of radioactive somatostatin analog binding to TtT-97 tumor tissue. Tissue samples in A, B, and C were exposed to 125I-labeled [Tyr3]SMS 201–995, which is a SSTR2- and SSTR5-selective ligand. D, E, and F are the same samples exposed to 125I-labeled [Leu8,D-Trp22,Tyr25]SRIF-28, which has high affinity for all SSTR subtypes 1–5. Tissues were from T4-treated (A, B, D, and E) or hypothyroid (C and F) animals. The samples in B and E were also exposed to an excess (10-6 M) of the respective unlabeled analog.

Effect of T₄ on steady state SSTR mRNA levels
Analysis of poly(A)⁺ mRNA from tumors of T₄-treated animals showed by Northern blotting (Fig. 2, upper panel) and confirmed by RT-PCR (Table 1) a consistent induction of SSTR1 and SSTR5 (RT-PCR shown in Fig. 3) message subtypes in TtT-97 tumors (n = 4) by thyroid hormone. A small amount of SSTR2 message was detected in 2 of the 4 T₄-treated tumors, but only after 45 PCR cycles (Table 1). The size of the transcripts encoding mSSTR1 [3.8 kilobases (kb)] corresponded with that reported in the literature for mouse type 1 receptor mRNA, and the putative mSSTR5 mRNA (2.6 kb) was similar in size to the rat homolog (12). Reprobing the same membrane with a TSHß cDNA confirmed the profound down-regulation of TSHß mRNA by thyroid hormone (Fig. 2, middle panel).

View larger version (73K): [in this window] [in a new window]   Figure 2. Northern blot analysis of poly(A)+ RNA from hypothyroid and T4-treated TtT-97 tumor tissue. Poly(A)+ RNA was isolated from TtT-97 tumor tissue, as described in Materials and Methods, and separated on an 1% denaturing agarose gel. After transfer to a nylon membrane, successive hybridization to the following radiolabeled cDNA probes was performed. Upper panel, mSSTR1 and rSSTR5; middle panel, mTSHß; lower panel, mouse ß-actin. Lanes 1 and 2, Baseline hypothyroid tumors; lanes 3 and 4, control hypothyroid tumors; lanes 5 and 6, T4-treated tumors. The Std lanes contains HindIII-digested DNA 32P-labeled size markers.

View larger version (36K): [in this window] [in a new window]   Figure 3. Detection of SSTR5 transcripts by RT-PCR analysis of RNA from TtT-97 tumors. Right panel, Total TtT-97 RNA from untreated and T4-treated animals was subjected to RT-PCR as described in Materials and Methods. Also shown are the PCR products with the same SSTR5 primers using plasmids containing SSTRs 1–5 as templates. The position of the expected 508-bp product is shown. G, Mouse genomic DNA as template; C, no added template. Lane M contains a 1-kb size marker ladder. Left panel, The same untreated and T4-treated RNA samples amplified with mouse ß-actin primers and the predicted 649-bp product are shown. M, G, and C are the same as in the right panel.

	Discussion

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The first notable finding in this study was that actively proliferating, TtT-97 thyrotropic tumor tissue, derived from hypothyroid mice had no consistent or significant expression of any somatostatin receptor subtype mRNA. Furthermore, ligand autoradiography confirmed the absence of cell surface somatostatin receptors. This was a surprising finding in view of the known role of native somatostatin in regulating physiological TSH secretion and by the efficacy of long-acting analogs of somatostatin in reducing TSH secretion from well documented cases of human TSH-producing tumors (20). However, earlier studies had shown that exogenous somatostatin had little effect on the elevated TSH levels of hypothyroid rats (21). Also, in 1983 Ridgway et al. (10) demonstrated that dispersed bovine pituitary cells showed a reduced efficacy of native somatostatin to decrease TSH secretion under hypothyroid conditions. In this same study, thyroid hormone administration produced a dose-dependent increase in the effectiveness of a single dose of native somatostatin-14 to suppress TRH-mediated TSH release (10). These observations suggested a testable hypothesis that thyroid hormone may play a pivotal role in regulating somatostatin receptor subtype expression in the TtT-97 model.

The second important finding in this study is that thyroid hormone supplementation of mice bearing the TtT-97 tumor resulted in the specific induction of SSTR1 and SSTR5 mRNA transcripts within the tumor. In addition, displaceable binding sites for somatostatin appeared on the cell surface of the thyrotropic tumor cells. As transcripts for SSTR1 and SSTR5 were demonstrated to go from undetectable to detectable levels by sensitive RT-PCR, this suggests a direct increase in transcriptional activity from these genes. Hinkle et al. (22) had previously shown a non-specific increase in ¹²⁵I-labeled Tyr¹ somatostatin-binding sites with T₃ treatment of GH₄C₁ cells, although it was not known whether this was due to an alteration in receptor number or binding affinity, nor was it known at the time that different subtypes of somatostatin receptors existed. Also, observations in a somatotroph-derived cell might not reflect SSTR regulation in the thyrotrope. It is well documented that thyroid hormone supplementation reduces TSH secretion and reverses thyrotrope hyperplasia in primary hypothyroidism. Similarly, thyroid hormone supplementation of radiothyroidectomized mice bearing TtT-97 tumors causes tumor involution (3). This indicates that the TtT-97 model closely resembles the normal thyrotrope and is a useful surrogate, which now provides a mechanism for thyroid hormone regulation of the TSH-secreting cell by somatostatin receptor induction.

Somatostatin receptor subtype gene expression has recently been described in the thyrotropes of euthyroid animals. For example, in situ hybridization studies in the normal rat have suggested that 57% of TSH-secreting cells express SSTR5, and 37% express SSTR2 (23), although SSTR1 expression was not assessed. Other investigators using similar techniques, but a different strain of rat, concluded by colocalization studies that all five SSTR mRNA subtypes were to be found in relationship to thyrotropes, but that SSTR2 (18%) was the most predominant (24). The type 5 receptor is known to have a particularly high affinity for somatostatin-28 (25). In addition, preferential SRIF-28-binding sites have been previously demonstrated in association with thyrotropes in the normal rat pituitary (26). Our findings of a predominant induction of SSTR5 in the Tt-T97 tumor would concur with these studies and highlights the importance of this particular subtype to the thyrotrope. The expression of a small amount of SSTR1 receptor would also be consistent with previous observations; however, the absence of the SSTR2 receptor is at variance with findings in the normal rat pituitary gland (23, 24).

Regulation of somatostatin receptor subtype expression by other hormones has previously been reported; for example, estrogen administration increases SSTR numbers and increases the sensitivity of PRL inhibition by exogenous somatostatin in cultured rat pituitary cells (27). Glucocorticoids affect SSTR expression in GH₄C₁ cells (28, 29). Such changes in SSTR mRNA abundance have been shown to be due to increased transcriptional activity with no alteration in message stability (29), our findings for thyroid hormone induction of SSTR1 and SSTR5 in the TtT-97 tumor would be consistent with this. It is likely that somatostatin receptor induction by different hormones is both a cell- and subtype-specific effect, hence underscoring the importance of the TtT-97 tumor as the only currently available model that reflects physiological thyrotrope function.

The promoter regions for rat SSTR1 and SSTR4 and human SSTR2 and SSTR5 have recently been published (30, 31, 32, 33). Although little is yet known of their functional effects, consensus DNA-binding elements for a variety of transcription factors have been identified. Interestingly, the rat SSTR1 promoter has a consensus TRE between -97 and -81 downstream from a Pit-1 recognition site. The published human SSTR5 promoter sequence (33) does not contain any discernible consensus TRE sites. No murine SSTR promoter regions have yet been described. Thus, the molecular mechanisms responsible for positive thyroid hormone induction of the SSTR1 and SSTR5 genes in the TtT-97 tumor are unknown and will require further study.

The mechanism of the antiproliferative effects of somatostatin and its analogs are potentially diverse (34, 35). However, a direct growth inhibitory effect has been clearly demonstrated via specific cell surface receptors for somatostatin in a variety of neuroendocrine tumors (36). SSTR1 mRNA expression has been shown in many types of human pituitary tumors (37, 38, 39) and is also present in normal pituitary (40). In addition, transcripts for SSTR subtypes 1, 2, and 5 have been demonstrated by RT-PCR in a high proportion of human somatotroph, lactotroph, corticotroph, and nonfunctioning pituitary tumors (38). As somatostatin receptor expression in pituitary tumors is invariably correlated with a therapeutic response to somatostatin analogs, expression of SSTR1 and SSTR5, coincident with a marked reduction in TtT-97 tumor size, is likely to be of great functional significance.

Octreotide, although capable of binding rodent type 2 and 5 receptor, has a poor affinity for the human type 5 receptor and shows little, if any, action at the SSTR1 receptor. This would suggest that, at least in human thyrotrope tumors, the antiproliferative and antisecretory actions are imparted via a different complement of SSTR isoforms from that found in the TtT-97 murine model. This also strengthens the view that the TtT-97 thyrotropic lesion might reflect a more hyperplastic, rather than tumorous, phenotype with a correspondingly different expression of SSTR subtypes

In summary, this study clearly shows that the actively proliferating murine TtT-97 thyrotropic tumor has an absence of SSTR expression under conditions of profound hypothyroidism. Treatment with thyroid hormone causes a reduction in tumor size and a decrease in TSH secretion along with the specific induction of mRNA for SSTR1 and SSTR5 and the appearance of displaceable binding sites for somatostatin-28 on the surface of the tumor. As such, this model can be used to further study the specific mechanisms by which thyroid hormone is able to influence the somatostatinergic system and how this controls antisecretory and antiproliferative effects in thyrotropic cells, especially with respect to the type 5 somatostatin receptor.

	Acknowledgments

 
We gratefully acknowledge donation of cDNA probes for SSTR subtypes by Dr. Graeme Bell, Howard Hughes Medical Institute, University of Chicago (Chicago, IL), and Dr. Michael Berelowitz and Dr. John Bruno, State University of New York (Stonybrook, NY). We also thank Dr. John Tentler for technical advice, and Suzanne Lewis for technical expertise.

	Footnotes

 
¹ This work was supported by grants from the Northern and Yorkshire Regional Health Authorities (to R.A.J.) and a travel fellowship from the Samuel Leonard-Simpson Memorial Trust, Royal College of Physicians (London, United Kingdom; to R.A.J.). Additional support was provided by NIH Grants DK-36842 (to E.C.R.), CA-47411 (to E.C.R.), and DK-02169 (to V.D.S.) and a grant from the Lucille P. Markey Charitable Trust.

² The IUPHAR nomenclature committee recently suggested that the previously used format for the somatostatin receptor subtypes, SSTR1-5, should be replaced with sst_1–5.

Received August 7, 1996.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 

1. Furth J, Moy P, Hershman JM, Ueda G 1973 Thyrotropic tumor syndrome. Arch Pathol 96:217–226[Medline]
2. Ross DS, Downing MF, Chin WW, Keiffer JD, Ridgway EC 1983 Divergent changes in murine pituitary concentration of free - and thyrotropin ß-subunits in hypothyroidism and after thyroxine administration. Endocrinology 112:187–193[Medline]
3. Sarapura VD, Wood MD, Gordon DF, Ridgway EC 1993 Effect of thyroid hormone on T₃-receptor mRNA levels and growth of thyrotropic tumours. Mol Cell Endocrinol 91:75–81[CrossRef][Medline]
4. Gershengorn MC 1978 Regulation of thyrotropin production by mouse pituitary tumor cells in vitro by physiological levels of thyroid hormones. Endocrinology 102:1122–1128[Medline]
5. Shupnik MA, Ridgway EC 1985 Triiodothyronine rapidly decreases transcription of thyrotropin subunit genes in thyrotropic tumor explants. Endocrinology 117:1940–1946[Abstract]
6. Marshall MC, Williams D, Weintraub BD 1981 Regulation of de novo biosynthesis of thyrotropin in normal, hyperplastic and neoplastic thyrotropes. Endocrinology 108:908–915[Medline]
7. Hershman JM, Pekary AE 1985 Regulation of thyrotropin secretion. In: Imura H (ed) The Pituitary Gland. Raven Press, New York, p 149
8. Comi RJ, Gesundheit N, Murray L, Gordon P, Weintraub BD 1987 Response of thyrotropin-secreting pituitary adenomas to a long-acting somatostatin analogue. N Engl J Med 317:12–17[Abstract]
9. Orme SM, Lamb JT, Nelson M, Belchetz PE 1991 Shrinkage of thyrotropin secreting pituitary adenoma treated with octreotide. Postgrad Med J 67:466–468[Abstract]
10. Ridgway EC, Klibanski A, Martorana MA, Milbury P, Kieffer JD, Chin WW 1983 The effect of somatostatin on the release of thyrotropin and its subunits from bovine anterior pituitary cells in vitro. Endocrinology 112:1937–1942[Abstract]
11. Hoyer D, Bell GI, Berelowitz M, Epelbaum J, Feniuk W, Humphrey P, O’Carroll, A-M, Patel YC, Schonbrunn A, Taylor JE, Reisine T 1995 Classification and nomenclature of somatostatin receptors. Trends Pharm Sci 16:85–87
12. Reisine T, Bell GI 1995 Molecular biology of the somatostatin receptors. Endocr Rev 16:427–442[CrossRef][Medline]
13. Bruns C, Weckbecker G, Raulf F, Kaupmann K, Schoeffter P, Hoyer D, Luppert H 1994 Molecular pharmacology of somatostatin receptor subtypes. Ann NY Acad Sci 733:138–146[Medline]
14. Gautvik KM, Tashjian AH, Kourides IA, Weintraub BD, Graeber CT, Maloof F, Suzuki K, Zuckerman JE 1974 Thyrotropin-releasing hormone is not the sole physiologic mediator of prolactin release during suckling. N Engl J Med 290:1162–1165
15. Wood WM, Ocran KO, Gordon DF, Ridgway EC 1991 Isolation and characterization of mouse complementary DNA’s encoding and ß thyroid hormone receptors from thyrotrope cells: the mouse pituitary-specific ß2 isoform differs at the amino terminus from the corresponding species from rat pituitary tumor cells. Mol Endocrinol 5:1049–1061[Abstract]
16. Raulf F, Pérez D, Hoyer C, Bruns C 1994 Differential expression of five somatostatin receptor subtypes, sst1–5, in the CNS and peripheral tissues. Digestion 55:46–53
17. Bruns C, Dietl M, Palacios JM, Pless J 1990 Identification and characterization of somatostatin receptors in neonatal rat long bones. Biochem J 265:39–44[Medline]
18. Kieffer JD, Ross DS, Shupnik MA, Ridgway EC 1985 Pure -subunit-secreting mouse pituitary tumor: inhibition of growth and secretion by combined treatment with thyroxine and bromocriptine. Endocrinology 117:1418–1423[Abstract]
19. Chin WW, Shupnik MA, Ross DS, Habner JF, Ridgway EC 1985 Regulation of the and thyrotropin ß-subunit messenger ribonucleic acids by thyroid hormones. Endocrinology 116:873–878[Abstract]
20. Beck-Peccoz P, Marriotti S, Guillausseau PJ, Medri G, Piscitelli G, Bertoli A, Barbarino A, Rondena M, Chanson P, Pinchera A, Faglia G 1989 Treatment of hyperthyroidism due to inappropriate secretion of thyrotropin with the somatostatin analogue SMS 201–995. J Clin Endocrinol Metab 68:208–214[Abstract]
21. Drouin J, De Lean A, Rainville D, Lachance R, Labrie F 1976 Characteristics of the interaction between thyrotropin-releasing hormone and somatostatin for thyrotropin and prolactin release. Endocrinology 98:514–521[Abstract]
22. Hinkle PM, Perrone MH, Schonbrunn A 1981 Mechanism of thyroid hormone inhibition of thyrotropin-releasing hormone action. Endocrinology 108:199–205[Abstract]
23. Day R, Dong W, Panetta R, Kracier J, Greenwood MT, Patel YC 1995 Expression of mRNA for somatostatin receptor (sst) types 2 and 5 in individual rat pituitary cells. A double labeling in situ hybridization analysis. Endocrinology 136:5232–5235[Abstract]
24. O’Carroll AM, Krempels K 1995 Widespread distribution of somatostatin messenger ribonucleic acid in rat pituitary. Endocrinology 136:5224–5227[Abstract]
25. O’Carroll AM, Raynor K, Lolait SJ, Reisine T 1994 Characterization of cloned human somatostatin receptor sst5. Mol Pharmacol 46:291–298[Abstract]
26. Morel G, Leroux P, Pelletier G 1985 Ultrastructural autoradiographic localization of somatostatin-28 in the rat anterior pituitary gland. Endocrinology 116:1615–1620[Abstract]
27. Kimura N, Hayafuji C, Kimura N 1989 Characterization of 17-ß-estradiol-dependent and -independent somatostatin receptor subtypes in the rat anterior pituitary. J Biol Chem 264:7033–7040[Abstract/Free Full Text]
28. Schonbrunn A 1982 Glucocorticoids down-regulate somatostatin receptors on pituitary cells in culture. Endocrinology 110:1147–1154[Medline]
29. Xu Y, Berelowitz M, Bruno JF 1995 Dexamethasone regulates somatostatin receptor subtype messenger ribonucleic acid expression in the rat pituitary GH₄C₁ cells. Endocrinology 136:5070–5075[Abstract]
30. Hauser F, Meyerhof W, Wulfsen I, Schönrock C, Richter D 1994 Sequence analysis of the promotor region of the rat somatostatin receptor subtype 1 gene. FEBS Let 345:225–228[CrossRef][Medline]
31. Xu Y, Bruno JF, Berelowitz M 1995 Characterization of the proximal promotor region of the rat somatostatin receptor gene, sst4. Biochem Biophys Res Commun 206:935–941[CrossRef][Medline]
32. Greenwood MT, Robertson L-A, Patel YC 1995 Cloning of the gene encoding human somatostatin receptor 2: sequence analysis of the 5'-flanking promotor region. Gene 159:291–292[CrossRef][Medline]
33. Greenwood MT, Panetta R, Robertson L-A, Liu JL, Patel YC 1994 Sequence analysis of the 5'-flanking promotor region of the human somatostatin receptor 5. Biochem Biophys Res Commun 205:1883–1890[CrossRef][Medline]
34. James RA, Weightman DR 1995 Somatostatin receptors: classification and subtypes in the pituitary. Endocrinologist 5:55–60
35. Reubi J-C, Laissue JA 1995 Multiple actions of somatostatin in neoplastic disease. Trends Pharm Sci 16:110–115[CrossRef][Medline]
36. Lamberts SW, Krenning EP, Reubi J 1991 The role of somatostatin and its analogs in the diagnosis and treatment of tumours. Endocr Rev 12:450–272[Medline]
37. Panetta R, Patel YC 1994 Expression of mRNA for all five human somatostatin receptors (hsst1–5) in pituitary tumors. Life Sci 56:333–342
38. Miller GM, Alexander JM, Bikkal H, Katznelson L, Zervas NT, Klibanski A 1995 Somatostatin receptor subtype gene expression in pituitary adenomas. J Clin Endocrinol Metab 80:1386–1392[Abstract]
39. Greenman Y, Melmed S 1994 Heterogenious expression of two somatostatin subtypes in pituitary tumours. J Clin Endocrinol Metab 78:398–403[Abstract]
40. Bruno JF, Xu Y, Song J, Berelowitz M 1993 Tissue distribution of somatostatin receptor subtype messenger ribonucleic acid in the rat. Endocrinology 133:2561–2567[Abstract]

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