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Briefings in Functional Genomics (1)
Molecular Biology of the Cell (1)
Molecular cancer therapeutics (1)
Andersen, Nicholas J. (3)
Duesbery, Nicholas S. (2)
Baker, Laurence H. (1)
Boguslawski, Elissa A. (1)
Bromberg-White, Jennifer L. (1)
Dawes, Michelle J. (1)
Dykema, Karl J. (1)
Froman, Roe E. (1)
Furge, Kyle A. (1)
Kamstock, Debra A. (1)
Kitchell, Barbara E. (1)
Krivochenitser, Roman I. (1)
Nickoloff, Brian J. (1)
Thomas, Dafydd G. (1)
Yeaman, Charles (1)
Year of Publication
Pharmacologic inhibition of MEK signaling prevents growth of canine hemangiosarcoma
Nickoloff, Brian J.
Dykema, Karl J.
Boguslawski, Elissa A.
Krivochenitser, Roman I.
Froman, Roe E.
Dawes, Michelle J.
Baker, Laurence H.
Thomas, Dafydd G.
Kamstock, Debra A.
Kitchell, Barbara E.
Furge, Kyle A.
Duesbery, Nicholas S.
Molecular cancer therapeutics
Angiosarcoma (AS) is a rare neoplasm of endothelial origin that has limited treatment options and poor five-year survival. As a model for human AS, we studied primary cells and tumorgrafts derived from canine hemangiosarcoma (HSA), which is also an endothelial malignancy with similar presentation and histology. Primary cells isolated from HSA showed constitutive ERK activation. The MEK inhibitor CI-1040 reduced ERK activation and the viability of primary cells derived from visceral, cutaneous, and cardiac HSA in vitro. HSA-derived primary cells were also sensitive to sorafenib, an inhibitor of B-Raf and multi-receptor tyrosine kinases. In vivo, CI-1040 or PD0325901 decreased the growth of cutaneous cell-derived xenografts and cardiac-derived tumorgrafts. Sorafenib decreased tumor size in both in vivo models, although cardiac tumorgrafts were more sensitive. In human AS, we noted that 50% of tumors stained positively for phosphorylated ERK1/2 and that the expression of several MEK-responsive transcription factors was up-regulated. Our data showed that MEK signaling is essential for the growth of HSA in vitro and in vivo and provided evidence that the same pathways are activated in human AS. This indicates that MEK inhibitors may form part of an effective therapeutic strategy for the treatment of canine HSA or human AS, and it highlights the utility of spontaneous canine cancers as a model of human disease.
Hemangiosarcoma; Angiosarcoma; MEK; ERK; CI-1040
MEK genomics in development and disease
Bromberg-White, Jennifer L.
Duesbery, Nicholas S.
Briefings in Functional Genomics
The mitogen-activated protein kinase kinases (the MAPK/ERK kinases; MKKs or MEKs) and their downstream substrates, the extracellular-regulated kinases have been intensively studied for their roles in development and disease. Until recently, it had been assumed any mutation affecting their function would have lethal consequences. However, the identification of MEK1 and MEK2 mutations in developmental syndromes as well as chemotherapy-resistant tumors, and the discovery of genomic variants in MEK1 and MEK2 have led to the realization the extent of genomic variation associated with MEKs is much greater than had been appreciated. In this review, we will discuss these recent advances, relating them to what is currently understood about the structure and function of MEKs, and describe how they change our understanding of the role of MEKs in development and disease.
MEK; MAPK; ERK; cardio-facial cutaneous syndrome; cancer; SNP
Sec3-containing Exocyst Complex Is Required for Desmosome Assembly in Mammalian Epithelial Cells
Molecular Biology of the Cell
In epithelial cells, Sec3 associates with Exocyst complexes enriched at desmosomes and centrosomes, distinct from Sec6/8 complexes at the apical junctional complex. RNAi-mediated suppression of Sec3 alters trafficking of desmosomal cadherins and impairs desmosome morphology and function, without noticeable effect on adherens junctions.
The Exocyst is a conserved multisubunit complex involved in the docking of post-Golgi transport vesicles to sites of membrane remodeling during cellular processes such as polarization, migration, and division. In mammalian epithelial cells, Exocyst complexes are recruited to nascent sites of cell–cell contact in response to E-cadherin–mediated adhesive interactions, and this event is an important early step in the assembly of intercellular junctions. Sec3 has been hypothesized to function as a spatial landmark for the development of polarity in budding yeast, but its role in epithelial cells has not been investigated. Here, we provide evidence in support of a function for a Sec3-containing Exocyst complex in the assembly or maintenance of desmosomes, adhesive junctions that link intermediate filament networks to sites of strong intercellular adhesion. We show that Sec3 associates with a subset of Exocyst complexes that are enriched at desmosomes. Moreover, we found that membrane recruitment of Sec3 is dependent on cadherin-mediated adhesion but occurs later than that of the known Exocyst components Sec6 and Sec8 that are recruited to adherens junctions. RNA interference-mediated suppression of Sec3 expression led to specific impairment of both the morphology and function of desmosomes, without noticeable effect on adherens junctions. These results suggest that two different exocyst complexes may function in basal–lateral membrane trafficking and will enable us to better understand how exocytosis is spatially organized during development of epithelial plasma membrane domains.
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