p62 Is Required for Stem Cell/Progenitor Retention through Inhibition of IKK/NF-κB/Ccl4 Signaling at the Bone Marrow Macrophage-Osteoblast Niche

Chang, Kyung Hee; Sengupta, Amitava; Nayak, Ramesh C.; Durán, Abraham Madroñal; Lee, Sang Jun; Pratt, Ronald G.; Wellendorf, Ashley M; Hill, Sarah E.; Watkins, Marcus; González‐Nieto, Daniel; Aronow, Bruce J.; Starczynowski, Daniel T.; Civitelli, Roberto; Diaz-Meco, Marı́a T.; Moscat, Jorge; Cancelas, José A.

doi:10.1016/j.celrep.2014.11.031

Cited by 60 publications

(55 citation statements)

References 67 publications

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“…Our data demonstrate that S100a8 acts upstream of Tlr4 and Tnfα in the Rps14 haploinsufficiency erythroid differentiation defect. Of note, RPS14 and miR-145 are universally co-deleted in the 5q- syndrome, and both converge on TLR4 signaling 25,40–44 , highlighting the cooperating effects of genes on 5q, as shown in Suppl. Figure 7.…”

Section: Discussionmentioning

confidence: 89%

Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8 and S100A9

Schneider

Schenone

Ferreira

et al. 2016

Nat Med

206

197

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Heterozygous deletion of RPS14 occurs in del(5q) MDS and has been linked to impaired erythropoiesis, characteristic of this disease subtype. We generated a murine model with conditional inactivation of Rps14 and demonstrated a p53-dependent erythroid differentiation defect with apoptosis at the transition from polychromatic to orthochromatic erythroblasts resulting in age-dependent progressive anemia, megakaryocyte dysplasia, and loss of hematopoietic stem cell (HSC) quiescence. Using quantitative proteomics, we identified significantly increased expression of proteins involved in innate immune signaling, particularly the heterodimeric S100a8/S100a9 proteins in purified erythroblasts. S100a8 expression was significantly increased in erythroblasts, monocytes and macrophages and recombinant S100a8 was sufficient to induce an erythroid differentiation defect in wild-type cells. We rescued the erythroid differentiation defect in Rps14 haploinsufficient HSCs by genetic inactivation of S100a8 expression. Our data link Rps14 haploinsufficiency to activation of the innate immune system via induction of S100A8/A9 and the p53-dependant erythroid differentiation defect in del(5q) MDS.

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Section: Discussionmentioning

confidence: 89%

Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8 and S100A9

Schneider

Schenone

Ferreira

et al. 2016

Nat Med

206

197

View full text Add to dashboard Cite

show abstract

“…1D and 1E). For this purpose, we generated RNA-seq data from normal breast epithelial cells (NBE) grown briefly in culture (GSE74417), and downloaded published RNA-seq data from normal colon (NC, GSM835561 (40)), and promyelocytes (PME, GSM1704844 (41)). Genes regulated by DAC had lower expression in cancer (YB5, MCF7, HL60) compared to its expression in normal tissue (NC, NBE, PME) (Student’s t-test, p < 0.05), while genes regulated by Depsi did not show this decrease (Student’s t-test, p > 0.05) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Transcriptional Selectivity of Epigenetic Therapy in Cancer

et al. 2017

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A central challenge in the development of epigenetic cancer therapy is the ability to direct selectivity in modulating gene expression for disease-selective efficacy. To address this issue, we characterized by RNA-seq, DNA methylation and ChIP-seq analyses the epigenetic response of a set of colon, breast and leukemia cancer cell lines to small molecule inhibitors against DNA methyltransferases (DAC), histone deacetylases (Depsi), histone demethylases (KDM1A inhibitor S2101), and histone methylases (EHMT2 inhibitor UNC0638 and EZH2 inhibitor GSK343). We also characterized the effects of DAC as combined with the other compounds. Averaged over the cancer cell models employed, we found that DAC affected 8.6% of the transcriptome and that 95.4% of the genes affected were upregulated. DAC preferentially regulated genes that were silenced in cancer and that were methylated at their promoters. In contrast, Depsi affected the expression of 30.4% of the transcriptome but showed little selectivity for gene upregulation or silenced genes. S2101, UNC0638, and GSK343 affected only 2% of the transcriptome, with UNC0638 and GSK343 preferentially targeting genes marked with H3K9me2 or H3K27me3, respectively. When combined with histone methylase inhibitors, the extent of gene upregulation by DAC was extended while still maintaining selectivity for DNA methylated genes and silenced genes. However, the genes upregulated by combination treatment exhibited limited overlap, indicating the possibility of targeting distinct sets of genes based on different epigenetic therapy combinations. Overall, our results demonstrated that DNA methyltransferase inhibitors preferentially target cancer-relevant genes and can be combined with inhibitors targeting histone methylation for synergistic effects while still maintaining selectivity.

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“…In addition to the TB domain, the UBA domain plays an important role in RANKL‐induced activation of NF‐κB as well as nuclear factor of activated T cells (NFAT) and ERK . However, p62 also inhibits NF‐κB activation in osteoblasts at several levels and is required for hematopoietic stem cell/progenitor retention in bone marrow . p62 also acts downstream to T‐cell receptor (TCR) activation and promotes allergic airway inflammation .…”

Section: P62‐mediated Signalingmentioning

confidence: 99%

p62/SQSTM1—Dr. Jekyll and Mr. Hyde that prevents oxidative stress but promotes liver cancer

et al. 2016

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p62/SQSTM1 is a multifunctional signaling hub and autophagy adaptor with many binding partners, which allow it to activate mTORC1-dependent nutrient sensing, NF-κB-mediated inflammatory responses and the NRF2-activated antioxidant defense. p62 recognizes polyubiquitin chains via its C-terminal domain and binds to LC3 via its LIR motif, thereby promoting the autophagic degradation of ubiquitinated cargos. p62 accumulates in many human liver diseases, including non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC), where it is a component of Mallory-Denk bodies and intracellular hyaline bodies. Chronic p62 elevation contributes to HCC development by preventing oncogene-induced senescence and death of cancer-initiating cells and enhancing their proliferation. In this review, we discuss p62-mediated signaling pathways and their roles in liver pathophysiology, especially NASH and HCC.

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p62 Is Required for Stem Cell/Progenitor Retention through Inhibition of IKK/NF-κB/Ccl4 Signaling at the Bone Marrow Macrophage-Osteoblast Niche

Cited by 60 publications

References 67 publications

Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8 and S100A9

Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8 and S100A9

Transcriptional Selectivity of Epigenetic Therapy in Cancer

p62/SQSTM1—Dr. Jekyll and Mr. Hyde that prevents oxidative stress but promotes liver cancer

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