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Experimental and molecular pathology (1)
Gene expression patterns : GEP (1)
Abichaker, George (2)
Htet, Khine (2)
Jaskoll, Tina (2)
Melnick, Michael (2)
Kaye, Frederic J (1)
Sedghizadeh, Parish (1)
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Small Molecule Inhibitors of the Host Cell COX/AREG/EGFR/ERK Pathway Attenuate Cytomegalovirus-induced Pathogenesis
Experimental and molecular pathology
As with other herpesviruses, human cytomegalovirus (hCMV) has the ability to establish lifelong persistence and latent infection following primary exposure, salivary glands (SMGs) being the primary site of both. In the immunocompromised patient, hCMV is a common cause of opportunistic infections, and subsequent morbidity and mortality. Elucidating the molecular pathogenesis of CMV-induced disease is critical to the development of more effective and safer drug therapies. In the present study, we used a novel mouse postnatal SMG organ culture model of mCMV-induced dysplasia to investigate a candidate signaling network suggested by our prior studies (COX-2/AREG/EGFR/ERK). The objective was to employ small molecule inhibitors to target several key steps in the autocrine loop, and in this way ameliorate pathology. Our results indicate that upregulation of ERK phosphorylation is necessary for initial mCMV-induced pathogenesis, and that ErbB receptor family phosphorylation and downstream signaling are highly relevant targets for drug discovery.
cytomegalovirus; CMV-induced pathology; COX-2; Amphiregulin; EGF receptor; ERK
CRTC1 Expression during Normal and Abnormal Salivary Gland Development Supports a Precursor Cell Origin for Mucoepidermoid Cancer
Kaye, Frederic J
Gene expression patterns : GEP
Dysregulation of the transcription factor CRTC1 by a t(11;19) chromosomal rearrangement mediates the formation of mucoepidermoid salivary gland carcinoma (MEC). Although the Crtc1 promoter is consistently active in fusion-positive MEC and low levels of Crtc1 transcripts have been reported in normal adult salivary glands, the distribution of CRTC1 protein in the normal salivary gland is not known. The aim of this study was to determine if CRTC1, like many known oncogenes, is expressed during early submandibular salivary gland (SMG) development and re-expressed in an experimental tumor model. Our results indicate that CRTC1 protein is expressed in SMG epithelia during early stages of morphogenesis, disappears with differentiation, and reappears in initial tumor-like pathology. This stage-dependent expression pattern suggests that CRTC1 may play a role during embryonic SMG branching morphogenesis but not for pro-acinar/acinar differentiation, supporting a precursor cell origin for MEC tumorigenesis. Moreover, the coincident expression of CRTC1 protein and cell proliferation markers in tumor-like histopathology suggests that CRTC1-mediated cell proliferation may contribute, in part, to initial tumor formation.
CREB coactivator; CRTC1; salivary glands; development; tumorigenesis; cell proliferation; mucoepidermoid carcinoma
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