Endocytosis of Proteins by Salivary Gland Duct Cells

Hand, Arthur R.; Coleman, Raymond; Mazariegos, M.R.; Lustmann, J.; Lotti, Lavinia Vittoria

doi:10.1177/00220345870660020501

Cited by 31 publications

(18 citation statements)

References 33 publications

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“…We next reasoned that if IL6 deficiency reduces senescence, then supplementation of IL6 into the submandibular gland may enhance senescence. In order to achieve increased local IL6 signaling in the salivary gland, IL6 protein was introduced via retrograde infusion through the salivary gland secretory duct (37). IL6 signaling depends on the expression of IL6R and its coreceptor, gp130, on target cells (38).…”

Section: Irradiated Il6mentioning

confidence: 99%

Radiation-Induced Loss of Salivary Gland Function Is Driven by Cellular Senescence and Prevented by IL6 Modulation

Marmary¹,

Adar²,

Gaska³

et al. 2016

Cancer Research

106

111

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Head and neck cancer patients treated by radiation commonly suffer from a devastating side effect known as dry-mouth syndrome, which results from the irreversible loss of salivary gland function via mechanisms that are not completely understood. In this study, we used a mouse model of radiationinduced salivary hypofunction to investigate the outcomes of DNA damage in the head and neck region. We demonstrate that the loss of salivary function was closely accompanied by cellular senescence, as evidenced by a persistent DNA damage response (gH2AX and 53BP1) and the expression of senescence-associated markers (SA-bgal, p19ARF, and DcR2) and secretory phenotype (SASP) factors (PAI-1 and IL6). Notably, profound apoptosis or necrosis was not observed in irradiated regions. Signs of cellular senescence were also apparent in irradiated salivary glands surgically resected from human patients who underwent radiotherapy. Importantly, using IL6 knockout mice, we found that sustained expression of IL6 in the salivary gland long after initiation of radiation-induced DNA damage was required for both senescence and hypofunction. Additionally, we demonstrate that IL6 pretreatment prevented both senescence and salivary gland hypofunction via a mechanism involving enhanced DNA damage repair. Collectively, these results indicate that cellular senescence is a fundamental mechanism driving radiation-induced damage in the salivary gland and suggest that IL6 pretreatment may represent a promising therapeutic strategy to preserve salivary gland function in head and neck cancer patients undergoing radiotherapy. Cancer Res; 76(5); 1170-80. Ó2016 AACR.

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Section: Irradiated Il6mentioning

confidence: 99%

Radiation-Induced Loss of Salivary Gland Function Is Driven by Cellular Senescence and Prevented by IL6 Modulation

Marmary¹,

Adar²,

Gaska³

et al. 2016

Cancer Research

106

111

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“…In line with a putative role for SMGC in the differentiation of mucin-producing acinar cells, these ductal cells may represent precursors to mucous cells found within mature excretory ducts (Pinkstaff 1980). Alternatively, salivary ductal cells have been shown to take up secreted acinar proteins via endocytosis (Hand et al 1987;Testa-Riva et al 1995).…”

Section: Discussionmentioning

confidence: 94%

Expression ofMuc19/SmgcGene Products During Murine Sublingual Gland Development: Cytodifferentiation and Maturation of Salivary Mucous Cells

Das

Cash

Hand

et al. 2008

J Histochem Cytochem.

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(ARH) S U M M A R Y Muc19/Smgc expresses two splice variants, Smgc (submandibular gland protein C) and Muc19 (mucin 19), the latter a major exocrine product of differentiated murine sublingual mucous cells. Transcripts for Smgc were detected recently in neonatal sublingual glands, suggesting that SMGC proteins are expressed during initial salivary mucous cell cytodifferentiation. We therefore compared developmental expression of transcripts and translation products of Smgc and Muc19 in sublingual glands. We find abundant expression of SMGC within the initial terminal bulbs, with a subsequent decrease as Muc19 expression increases. During postnatal gland expansion, SMGC is found in presumptive newly formed acinar cells and then persists in putative acinar stem cells. Mucin levels increase 7-fold during the first 3 weeks of life, with little change in transcript levels, whereas between postnatal days 21 and 28, there is a 3-fold increase in Muc19 mRNA and heteronuclear RNA. Our collective results demonstrate the direct transition from SMGC to Muc19 expression during early mucous cell cytodifferentiation and further indicate developmentally regulated changes in Muc19/Smgc transcription, alternative splicing, and translation. These changes in Muc19/Smgc gene expression delineate multiple stages of salivary mucous cell cytodifferentiation and subsequent maturation during embryonic gland development through the first 4 weeks of postnatal life. (J Histochem Cytochem 57:383-396, 2009)

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“…After 1 hour, the glands were removed and processed for immunocytochemistry. The actin cytoskeleton was labeled to identify the various types of epithelial cells in the salivary glands, based on their morphology (Hand et al, 1987; Matsuoka et al, 2000; Sramkova et al, 2009). In the absence of rAd5, labeled DNA was found in all the cells of the parenchyma (Fig.…”

Section: Resultsmentioning

confidence: 99%

Plasmid DNA is internalized from the apical plasma membrane of the salivary gland epithelium in live animals

Šrámková

Masedunskas

Weigert

2012

Histochem Cell Biol

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Non viral-mediated gene delivery represents an alternative way to express the gene of interest without inducing immune responses or other adverse effects. Understanding the mechanisms by which plasmid DNAs are delivered to the proper target in vivo is a fundamental issue that needs to be addressed in order to design more effective strategies for gene therapy. As a model system, we have used the submandibular salivary glands in live rats and we have recently shown that reporter transgenes can be expressed in different cell populations of the glandular epithelium, depending on the modality of administration of plasmid DNA. Here, by using a combination of immunofluorescence and intravital microscopy, we have explored the relationship between the pattern of transgenes expression and the internalization of plasmid DNA. We found that plasmid DNA is internalized: 1) by all the cells in the salivary gland epithelium, when administered alone 2) by large ducts, when mixed with empty adenoviral particles, and 3) by acinar cells upon stimulation of compensatory endocytosis. Moreover, we showed that plasmid DNA utilizes different routes of internalization, and evades both the lysosomal degradative pathway and the retrograde pathway towards the Golgi apparatus. This study clearly shows that in vivo approaches have the potential to address fundamental questions on the cellular mechanisms regulating gene delivery.

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Endocytosis of Proteins by Salivary Gland Duct Cells

Cited by 31 publications

References 33 publications

Radiation-Induced Loss of Salivary Gland Function Is Driven by Cellular Senescence and Prevented by IL6 Modulation

Radiation-Induced Loss of Salivary Gland Function Is Driven by Cellular Senescence and Prevented by IL6 Modulation

Expression ofMuc19/SmgcGene Products During Murine Sublingual Gland Development: Cytodifferentiation and Maturation of Salivary Mucous Cells

Plasmid DNA is internalized from the apical plasma membrane of the salivary gland epithelium in live animals

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