FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W3208556323> ?p ?o ?g. }

• W3208556323 endingPage "61" @default.
• W3208556323 startingPage "50" @default.
• W3208556323 abstract "•Increased levels of intracellular unbound heme is found in an Rps19-deficient mouse model for DBA•Reduced levels of Eukaryotic translation initiation factor 2-alpha kinase 1 (HRI) dampen elevated levels of unbound intracellular heme and ameliorates p53 activation in Rps19-deficient erythroblasts•Treatment with alpha-1-microglobulin (A1M) decreases unbound intracellular heme without affecting p53 activity in Rps19-deficient cells Diamond-Blackfan anemia (DBA) is a rare genetic disorder in which patients present a scarcity of erythroid precursors in an otherwise normocellular bone marrow. Most, but not all, patients carry mutations in ribosomal proteins such as RPS19, suggesting that compromised mRNA translation and ribosomal stress are pathogenic mechanisms causing depletion of erythroid precursors. To gain further insight to disease mechanisms in DBA, we performed a custom short hairpin RNA (shRNA) based screen against 750 genes hypothesized to affect DBA pathophysiology. Among the hits were two shRNAs against the erythroid specific heme-regulated eIF2α kinase (HRI), which is a negative regulator of mRNA translation. This study shows that shRNA-mediated HRI silencing or loss of one HRI allele improves expansion of Rps19-deficient erythroid precursors, as well as improves the anemic phenotype in Rps19-deficient animals. We found that Rps19-deficient erythroblasts have elevated levels of unbound intracellular heme, which is normalized by HRI heterozygosity. Additionally, targeting elevated heme levels by treating cells with the heme scavenger alpha-1-microglobulin (A1M), increased proliferation of Rps19-deficient erythroid precursors and decreased heme levels in a disease-specific manner. HRI heterozygosity, but not A1M treatment, also decreased the elevated p53 activity observed in Rps19-deficient cells, indicating that p53 activation is caused by ribosomal stress and aberrant mRNA translation and not heme overload in Rps19-deficiency. Together, these findings suggest that targeting elevated heme levels is a promising new treatment strategy for DBA. Diamond-Blackfan anemia (DBA) is a rare genetic disorder in which patients present a scarcity of erythroid precursors in an otherwise normocellular bone marrow. Most, but not all, patients carry mutations in ribosomal proteins such as RPS19, suggesting that compromised mRNA translation and ribosomal stress are pathogenic mechanisms causing depletion of erythroid precursors. To gain further insight to disease mechanisms in DBA, we performed a custom short hairpin RNA (shRNA) based screen against 750 genes hypothesized to affect DBA pathophysiology. Among the hits were two shRNAs against the erythroid specific heme-regulated eIF2α kinase (HRI), which is a negative regulator of mRNA translation. This study shows that shRNA-mediated HRI silencing or loss of one HRI allele improves expansion of Rps19-deficient erythroid precursors, as well as improves the anemic phenotype in Rps19-deficient animals. We found that Rps19-deficient erythroblasts have elevated levels of unbound intracellular heme, which is normalized by HRI heterozygosity. Additionally, targeting elevated heme levels by treating cells with the heme scavenger alpha-1-microglobulin (A1M), increased proliferation of Rps19-deficient erythroid precursors and decreased heme levels in a disease-specific manner. HRI heterozygosity, but not A1M treatment, also decreased the elevated p53 activity observed in Rps19-deficient cells, indicating that p53 activation is caused by ribosomal stress and aberrant mRNA translation and not heme overload in Rps19-deficiency. Together, these findings suggest that targeting elevated heme levels is a promising new treatment strategy for DBA." @default.
• W3208556323 created "2021-11-08" @default.
• W3208556323 creator A5007631856 @default.
• W3208556323 creator A5030636952 @default.
• W3208556323 creator A5036706255 @default.
• W3208556323 creator A5044026012 @default.
• W3208556323 creator A5053838272 @default.
• W3208556323 creator A5054738281 @default.
• W3208556323 creator A5061354683 @default.
• W3208556323 creator A5079118909 @default.
• W3208556323 creator A5082857859 @default.
• W3208556323 creator A5087490874 @default.
• W3208556323 creator A5090329098 @default.
• W3208556323 date "2022-01-01" @default.
• W3208556323 modified "2023-10-14" @default.
• W3208556323 title "Targeting elevated heme levels to treat a mouse model for Diamond-Blackfan Anemia" @default.
• W3208556323 cites W1497167438 @default.
• W3208556323 cites W1501957186 @default.
• W3208556323 cites W1521601785 @default.
• W3208556323 cites W1827920754 @default.
• W3208556323 cites W1881873400 @default.
• W3208556323 cites W1963795701 @default.
• W3208556323 cites W1964632456 @default.
• W3208556323 cites W1965313133 @default.
• W3208556323 cites W1977605312 @default.
• W3208556323 cites W1991631517 @default.
• W3208556323 cites W1993335425 @default.
• W3208556323 cites W1993501781 @default.
• W3208556323 cites W2004219583 @default.
• W3208556323 cites W2008407032 @default.
• W3208556323 cites W2010946709 @default.
• W3208556323 cites W2018642899 @default.
• W3208556323 cites W2020207911 @default.
• W3208556323 cites W2026733551 @default.
• W3208556323 cites W2038881587 @default.
• W3208556323 cites W2039516373 @default.
• W3208556323 cites W2043545270 @default.
• W3208556323 cites W2049667730 @default.
• W3208556323 cites W2051933574 @default.
• W3208556323 cites W2063231360 @default.
• W3208556323 cites W2072320556 @default.
• W3208556323 cites W2073586815 @default.
• W3208556323 cites W2074928689 @default.
• W3208556323 cites W2082940727 @default.
• W3208556323 cites W2085280576 @default.
• W3208556323 cites W2091571816 @default.
• W3208556323 cites W2095477436 @default.
• W3208556323 cites W2103961722 @default.
• W3208556323 cites W2112706571 @default.
• W3208556323 cites W2112915311 @default.
• W3208556323 cites W2116086627 @default.
• W3208556323 cites W2116844389 @default.
• W3208556323 cites W2128773662 @default.
• W3208556323 cites W2133832061 @default.
• W3208556323 cites W2139529165 @default.
• W3208556323 cites W2141455745 @default.
• W3208556323 cites W2143881989 @default.
• W3208556323 cites W2149046852 @default.
• W3208556323 cites W2160451402 @default.
• W3208556323 cites W2359149763 @default.
• W3208556323 cites W2530054587 @default.
• W3208556323 cites W2741508285 @default.
• W3208556323 cites W2793151925 @default.
• W3208556323 cites W2793800931 @default.
• W3208556323 cites W2884535700 @default.
• W3208556323 cites W2915140666 @default.
• W3208556323 cites W2942563094 @default.
• W3208556323 doi "https://doi.org/10.1016/j.exphem.2021.10.005" @default.
• W3208556323 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/34757171" @default.
• W3208556323 hasPublicationYear "2022" @default.
• W3208556323 type Work @default.
• W3208556323 sameAs 3208556323 @default.
• W3208556323 citedByCount "3" @default.
• W3208556323 countsByYear W32085563232022 @default.
• W3208556323 countsByYear W32085563232023 @default.
• W3208556323 crossrefType "journal-article" @default.
• W3208556323 hasAuthorship W3208556323A5007631856 @default.
• W3208556323 hasAuthorship W3208556323A5030636952 @default.
• W3208556323 hasAuthorship W3208556323A5036706255 @default.
• W3208556323 hasAuthorship W3208556323A5044026012 @default.
• W3208556323 hasAuthorship W3208556323A5053838272 @default.
• W3208556323 hasAuthorship W3208556323A5054738281 @default.
• W3208556323 hasAuthorship W3208556323A5061354683 @default.
• W3208556323 hasAuthorship W3208556323A5079118909 @default.
• W3208556323 hasAuthorship W3208556323A5082857859 @default.
• W3208556323 hasAuthorship W3208556323A5087490874 @default.
• W3208556323 hasAuthorship W3208556323A5090329098 @default.
• W3208556323 hasBestOaLocation W32085563231 @default.
• W3208556323 hasConcept C104317684 @default.
• W3208556323 hasConcept C105580179 @default.
• W3208556323 hasConcept C149364088 @default.
• W3208556323 hasConcept C153911025 @default.
• W3208556323 hasConcept C161238802 @default.
• W3208556323 hasConcept C181199279 @default.
• W3208556323 hasConcept C184235292 @default.
• W3208556323 hasConcept C190232843 @default.
• W3208556323 hasConcept C2776217839 @default.
• W3208556323 hasConcept C2778997081 @default.

• next