The endocrine secretion of mammalian digestive enzymes by exocrine glands

Isenman, Lois; Liebow, Charles; Rothman, Stephen

doi:10.1152/ajpendo.1999.276.2.e223

Cited by 54 publications

(59 citation statements)

References 47 publications

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“…Conversely, only a modest amount of hPTH was found in the saliva of these mice, that is, hPTH secretion was primarily in an endocrine direction in mouse salivary glands. Although less commonly considered, secretion into the bloodstream from the salivary glands is well described and occurs via illdefined basolateral secretory pathways (Kagami et al, 1996;Baum et al, 1999;Isenman et al, 1999;Gorr et al, 2005). The immunofluorescent staining of transduced mouse glands revealed a significant accumulation of hPTH on the basolateral side of parenchymal cells, consistent with the hypothe-…”

Section: Figsupporting

confidence: 66%

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Differential Sorting of Human Parathyroid Hormone After Transduction of Mouse and Rat Salivary Glands

et al. 2008

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Gene transfer to salivary glands leads to abundant secretion of transgenic protein into either saliva or the bloodstream. This indicates significant clinical potential, depending on the route of sorting. The aim of this study was to probe the sorting characteristics of human parathyroid hormone (hPTH) in two animal models for salivary gland gene transfer. PTH is a key hormone regulating calcium levels in the blood. A recombinant serotype 5 adenoviral vector carrying the hPTH cDNA was administered to the submandibular glands of mice and rats. Two days after delivery, high levels of hPTH were found in the serum of mice, leading to elevated serum calcium levels. Only low amounts of hPTH were found in the saliva. Two days after vector infusion into rats, a massive secretion of hPTH was measured in saliva, with little secretion into serum. Confocal microscopy showed hPTH in the glands, localized basolaterally in mice and apically in rats. Submandibular gland transduction was effective and the produced hPTH was biologically active in vivo. Whereas hPTH sorted toward the basolateral side in mice, in rats hPTH was secreted mainly at the apical side. These results indicate that the interaction between hPTH and the cell sorting machinery is different between mouse and rat salivary glands. Detailed studies in these two species should result in a better understanding of cellular control of transgenic secretory protein sorting in this tissue.

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Section: Figsupporting

confidence: 66%

“…However, salivary glands can secrete exocrine and endocrine proteins to either the apical pole or the basolateral pole of the cells (Lawrence et al, 1977;Leonora et al, 1987;Baum et al, 1999;Isenman et al, 1999). Unfortunately, the direction of this secretion is not readily predictable for all transgenic proteins.…”

mentioning

confidence: 99%

Differential Sorting of Human Parathyroid Hormone After Transduction of Mouse and Rat Salivary Glands

et al. 2008

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“…Although it would seem surprising that a presumptive endocrine factor is strongly expressed in an exocrine gland, there have been numerous reports of other growth factors being expressed in salivary glands (15)(16)(17)(18)(19), and it has been shown that endocrine factors expressed after introduction of DNA into these glands are readily secreted into the bloodstream (20,21). Indeed, a body of opinion contends that salivary glands have a mixed exocrine and endocrine function (22)(23)(24). Similarly, we also saw expression in the lacrimal glands of newborn mice.…”

Section: Resultsmentioning

confidence: 99%

Resistance to diet-induced obesity in mice globally overexpressing OGH/GPB5

Macdonald

Wortley

Gowen

et al. 2005

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

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We identified a glycoprotein hormone ␤-subunit (OGH, also called GPB5) that, as a heterodimer with the ␣-subunit GPA2, serves as a second ligand for the thyroid-stimulating hormone receptor. Mice in which the OGH gene is deleted (OGH ؊/؊ ) are indistinguishable from WT littermates in body weight, response to high-fat diet, metabolic parameters, body composition, and insulin tolerance. Mice engineered to transgenically globally overexpress OGH (OGH-TG) develop Ϸ2-fold elevations in their basal thyroid levels and weigh slightly less than WT littermates despite increased food intake because of an increase in their metabolic rates. Moreover, when OGH-TG mice are challenged with a high-fat diet, they gain significantly less weight and body fat than their WT littermates. The OGH-TG mice also have reduced blood glucose, insulin, cholesterol, and triglycerides. In contrast to other approaches in which the thyroid axis is activated, OGH-TG mice exhibit only minor changes in heart rate and blood pressure. Our findings suggest that constitutive low-level activation of the thyroid axis (via OGH or other means) may provide a beneficial therapeutic approach for combating diet-induced obesity.cholesterol ͉ metabolic rate ͉ thyroid T hyroid-stimulating hormone (TSH) and the TSH receptor (TSHR) are key proteins in the control of thyroid function. TSH synthesis and release is stimulated by hypothalamic TSHreleasing hormone (TRH) and is down-regulated (inhibited) by thyroid hormone in a classic endocrine negative-feedback loop. The specificity inherent in TSH resides in its unique ␤-subunit that heterodimerizes with a common ␣-subunit, which it shares with the other glycoprotein hormones [i.e., follicle-stimulating hormone (FSH), luteinizing hormone, and chorionic gonadotropin]. The primary physiological actions of TSH on the thyroid are stimulation of the synthesis and release of 3,5,3Ј,5Ј-tetraiodo-L-thyronine (T4) and 3,5,3Ј-triiodo-L-thyronine (T3) (together termed thyroid hormone) and promotion of thyroid growth; for example, it has been shown that thyroid development is arrested in mice with targeted disruption of the common ␣-subunit (1).Clinically, thyroid hormone is used primarily as a replacement therapy for the patients with hypothyroidism, and it has been considered as a possible therapy for weight reduction (because of its ability to increase metabolism and energy expenditures), for lowering cholesterol, and even to build bone (in osteoporosis). One of the major hurdles in this approach has been the cardiovascular toxicity observed after administration of the endogenous ligands T4 and T3 or nonselective thyroid hormone agonists. The two major subtypes of the thyroid hormone receptors that mediate these responses, TR␣ and TR␤, are the products of different genes and are also differentially processed to each yield two isoforms. It has been argued that modulation of heart rate and rhythm is mediated predominantly by activation of TR␣ 1 (2-4), and as a result, recent pharmaceutical research efforts have focused on develop...

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“…These lead to specific sorting routes for transgenic secretory proteins in an endocrine and exocrine manner [16]. For example, human growth hormone (hGH), which in the anterior pituitary gland is secreted into the bloodstream via the RSP, when expressed from an adenoviral vector delivered to rodent and miniature pig salivary glands, follows the tissue specific RSP, i.e., the exocrine route into saliva [17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Sorting of growth hormone–erythropoietin fusion proteins in rat salivary glands

Samuni

Zheng

Cawley

et al. 2008

Biochemical and Biophysical Research Communications

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Neuroendocrine and exocrine cells secrete proteins in either a constitutive manner or via the regulated secretory pathway (RSP), but the specific sorting mechanisms involved are not fully understood. After gene transfer to rat salivary glands, the transgenic model proteins human growth hormone (hGH) and erythropoietin (hEpo) are secreted primarily into saliva (RSP; exocrine) and serum (constitutive; endocrine), respectively. We hypothesized that fusion of hGH at either the C-terminus or the N-terminus of hEpo would re-direct hEpo from the bloodstream into saliva. We constructed and expressed two fusion proteins, hEpo-hGH and hGH-hEpo, using serotype 5-adenoviral vectors, and delivered them to rat submandibular glands in vivo via retroductal cannulation. Both the hEpohGH and hGH-hEpo fusion proteins, but not hEpo alone, were secreted primarily into saliva (p<0.0001 and P=0.0083, respectively). These in vivo studies demonstrate for the first time that hGH, in an N-as well as C-terminal position, influences the secretion of a constitutive pathway protein.

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The endocrine secretion of mammalian digestive enzymes by exocrine glands

Cited by 54 publications

References 47 publications

Differential Sorting of Human Parathyroid Hormone After Transduction of Mouse and Rat Salivary Glands

Differential Sorting of Human Parathyroid Hormone After Transduction of Mouse and Rat Salivary Glands

Resistance to diet-induced obesity in mice globally overexpressing OGH/GPB5

Sorting of growth hormone–erythropoietin fusion proteins in rat salivary glands

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