Smarca5, an ATPase of the ISWI class of chromatin remodelers, is a key regulator of chromatin structure, cell cycle and DNA repair. Smarca5 is deregulated in leukemia and breast, lung and gastric cancers. However, its role in oncogenesis is not well understood. Chromatin remodelers often play dosage-dependent roles in cancer. We therefore investigated the epigenomic and phenotypic impact of controlled stepwise attenuation of Smarca5 function in the context of primary cell transformation, a process relevant to tumor formation. Upon conditional single- or double-allele Smarca5 deletion, the cells underwent both accelerated growth arrest and senescence entry and displayed gradually increased sensitivity to genotoxic insults. These phenotypic characteristics were explained by specific remodeling of the chromatin structure and the transcriptome in primary cells prior to the immortalization onset. These molecular programs implicated Smarca5 requirement in DNA damage repair, telomere maintenance, cell cycle progression and in restricting apoptosis and cellular senescence. Consistent with the molecular programs, we demonstrate for the first time that Smarca5-deficient primary cells exhibit dramatically decreased capacity to bypass senescence and immortalize, an indispensable step during cell transformation and cancer development. Thus, Smarca5 plays a crucial role in key homeostatic processes and sustains cancer-promoting molecular programs and cellular phenotypes.

• MeSH
• adenosintrifosfatasy metabolismus   MeSH
• chromatin * MeSH
• nádory * MeSH
• oprava DNA MeSH
• poškození DNA MeSH
• restrukturace chromatinu MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Erythropoietin (EPO) downregulates hepcidin expression to increase the availability of iron; the downregulation of hepcidin is mediated by erythroferrone (ERFE) secreted by erythroblasts. Erythroblasts also express transferrin receptor 2 (TFR2); however, the possible role of TFR2 in hepcidin downregulation is unclear. The purpose of the study was to correlate liver expression of hepcidin with the expression of ERFE and TFR2 in murine bone marrow and spleen at 4, 16, 24, 48, 72 and 96 h following administration of a single dose of EPO. Splenic Fam132b expression increased 4 h after EPO injection; liver hepcidin mRNA was decreased at 16 h. In the spleen, expression of TFR2 and transferrin receptor (TFR1) proteins increased by an order of magnitude at 48 and 72 h after EPO treatment. The EPO-induced increase in splenic TFR2 and TFR1 was associated with an increase in the number of Tfr2- and Tfr1-expressing erythroblasts. Plasma exosomes prepared from EPO-treated mice displayed increased amount of TFR1 protein; however, no exosomal TFR2 was detected. Overall, the results confirm the importance of ERFE in stress erythropoiesis, support the role of TFR2 in erythroid cell development, and highlight possible differences in the removal of TFR2 and TFR1 from erythroid cell membranes.

• MeSH
• cytokiny genetika   metabolismus   MeSH
• erythropoetin farmakologie   MeSH
• erytroblasty účinky léků   metabolismus   MeSH
• exozómy metabolismus   MeSH
• hepcidiny genetika   metabolismus   MeSH
• játra metabolismus   MeSH
• kultivované buňky MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• receptory transferinu genetika   metabolismus   MeSH
• slezina metabolismus   MeSH
• svalové proteiny genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Matriptase-2, a serine protease expressed in hepatocytes, is a negative regulator of hepcidin expression. The purpose of the study was to investigate the interaction of matriptase-2 with hemojuvelin protein in vivo. Mice lacking the matriptase-2 proteolytic activity (mask mice) display decreased content of hemojuvelin protein. Vice versa, the absence of hemojuvelin results in decreased liver content of matriptase-2, indicating that the two proteins interact. To further characterize the role of matriptase-2, we investigated iron metabolism in mask mice fed experimental diets. Administration of iron-enriched diet increased liver iron stores as well as hepcidin expression. Treatment of iron-overloaded mask mice with erythropoietin increased hemoglobin and hematocrit, indicating that the response to erythropoietin is intact in mask mice. Feeding of an iron-deficient diet to mask mice significantly increased spleen weight as well as the splenic content of erythroferrone and transferrin receptor proteins, indicating stress erythropoiesis. Liver hepcidin expression was decreased; expression of Id1 was not changed. Overall, the results suggest a complex interaction between matriptase-2 and hemojuvelin, and demonstrate that hepcidin can to some extent be regulated even in the absence of matriptase-2 proteolytic activity.

• MeSH
• deficit železa MeSH
• dietní železo farmakologie   MeSH
• erythropoetin farmakologie   MeSH
• GPI-vázané proteiny biosyntéza   nedostatek   genetika   fyziologie   MeSH
• hepcidiny biosyntéza   genetika   MeSH
• inhibitor diferenciace 1 biosyntéza   genetika   MeSH
• játra metabolismus   MeSH
• kostní morfogenetický protein 6 biosyntéza   genetika   MeSH
• membránové proteiny nedostatek   genetika   fyziologie   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• orgánová specificita MeSH
• přetížení železem metabolismus   MeSH
• promotorové oblasti (genetika) genetika   MeSH
• protein hemochromatózy biosyntéza   nedostatek   genetika   fyziologie   MeSH
• proteinové domény MeSH
• regulace genové exprese účinky léků   MeSH
• rekombinantní proteiny metabolismus   MeSH
• serinové endopeptidasy nedostatek   genetika   fyziologie   MeSH
• slezina metabolismus   MeSH
• železo MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH