The KIT/c-KIT proto-oncogene is frequently over-expressed in Merkel cell carcinoma (MCC), an aggressive skin cancer commonly caused by Merkel cell polyomavirus (MCPyV). Here, we demonstrated that trun Show more
The KIT/c-KIT proto-oncogene is frequently over-expressed in Merkel cell carcinoma (MCC), an aggressive skin cancer commonly caused by Merkel cell polyomavirus (MCPyV). Here, we demonstrated that truncated MCPyV-encoded large T-antigen (LT) suppressed macroautophagy/autophagy by stabilizing and sequestering KIT in the paranuclear compartment via binding VPS39. KIT engaged with phosphorylated BECN1, thereby enhancing its association with BCL2 while diminishing its interaction with the PIK3C3 complex. This process ultimately resulted in the suppression of autophagy. Depletion of KIT triggered both autophagy and apoptosis, and decreased LT expression. Conversely, blocking autophagy in KIT-depleted cells restored LT levels and rescued apoptosis. Additionally, stimulating autophagy efficiently increased cell death and inhibited tumor growth of MCC xenografts in mice. These insights into the interplay between MCPyV LT and autophagy regulation reveal important mechanisms by which viral oncoproteins are essential for MCC cell viability. Thus, autophagy-inducing agents represent a therapeutic strategy in advanced MCPyV-associated MCC. Show less
Syndecans belong to a four-member family of cell surface heparan sulfate proteoglycans (HSPGs) abundantly present in various tissues. They are primarily recognized as extracellular matrix (ECM) recept Show more
Syndecans belong to a four-member family of cell surface heparan sulfate proteoglycans (HSPGs) abundantly present in various tissues. They are primarily recognized as extracellular matrix (ECM) receptors able to bind various ECM components and form gradients of morphogens and growth factors. Syndecans are composed of core protein with distinctive cytoplasmic, transmembrane, and extracellular domains to which several HS glycosaminoglycan (GAG) chains are covalently attached. In development of composite organs, such as teeth, expression patterns of syndecans display temporo-spatial shifts between epithelial and mesenchymal tissue compartments. Along with diverse functional properties of syndecans and generally large number of their interactors due to HS GAG chain content, this suggests possible involvement of syndecans in modulation of epithelial-to-mesenchymal crosstalk. Functional versatility of syndecans greatly depends upon the biochemical properties of attached HS GAG chains. These are specifically determined during the HS biosynthesis by the combinatorial action of glycosyl-transferases (Exts/EXTs) and bi-functional sulfotransferases (Ndsts/NDSTs), as well as by post-biosynthetic enzymatic cleavage of HS by the only active endoglucuronidase in mammals, heparanase 1 (Hpse1/HPSE1). Matching the essential requirement for HS during organogenesis, null-mutant animals for genes encoding these enzymes display severe developmental anomalies of mineralized tissues (including teeth) with embryonic or perinatal lethality. In this study, we analyzed expression of syndecan HSPGs (syndecans 1, 2, and 4), enzymes involved in HS biosynthesis (EXT1, NDST1, NDST2) and HS cleavage (HPSE1) in human tooth germs during the early stages of odontogenesis. All of the investigated factors displayed temporo-spatial differences in expression patterns, and some of them showed distinctive asymmetries of expression domains. Our findings suggest that these factors might be differentially involved in cellular processes which take place during the early odontogenic sequence in humans. Show less