The Role of Activin A in Regulation of Hemopoiesis

Shav‐Tal, Yaron; Zipori, Dov

doi:10.1634/stemcells.20-6-493

Cited by 62 publications

(15 citation statements)

References 79 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Type 1 collagen, the main osteogenic collagen was not amongst the regulated genes, however, multiple other osteogenic markers genes including aggrecan (ACAN), sparc/osteonectin (SPOCK1), osteoblast cadherin (CDH11) and Wnt pathway members Frizzled homologue-8 (FZD8) and Secreted frizzled related protein 4 (SFRP4) were induced in parallel with decreased expression of the negative osteogenic regulator osteocrin (Tables 2 and 3 ) [ 52 , 53 ]. Four of the most strongly induced genes including early growth response 2 (EGR2 > 6-fold) [ 54 ], interleukin 11 (Il-11 > 5-fold), growth differentiation factor 6 (GDF6 > 5-fold) and hemopoietic cell kinase (HCK ~5-fold) as well as activin-A receptor (2-fold [ 55 ]) are associated with hematopoiesis. Transcript levels of multiple genes associated with angiogenesis were increased by hypoxia [ 56 ] while there were marked decreases of multiple striated muscle markers (Tables 2 and 3 ).…”

Section: Resultsmentioning

confidence: 99%

Severe hypoxia exerts parallel and cell-specific regulation of gene expression and alternative splicing in human mesenchymal stem cells

Shehadeh

et al. 2014

BMC Genomics

View full text Add to dashboard Cite

BackgroundThe endosteum of the bone marrow provides a specialized hypoxic niche that may serve to preserve the integrity, pluripotency, longevity and stemness of resident mesenchymal stem cells (MSCs). To explore the molecular genetic consequences of such a niche we subjected human (h) MSCs to a pO2 of 4 mmHg and analyzed global gene expression and alternative splicing (AS) by genome-exon microarray and RT-qPCR, and phenotype by western blot and immunostaining.ResultsOut of 446 genes differentially regulated by >2.5-fold, down-regulated genes outnumbered up-regulated genes by 243:203. Exon analyses revealed 60 hypoxia-regulated AS events with splice indices (SI) >1.0 from 53 genes and a correlation between high SI and degree of transcript regulation. Parallel analyses of a publicly available AS study on human umbilical vein endothelial cells (HUVECs) showed that there was a strong cell-specific component with only 11 genes commonly regulated in hMSCs and HUVECs and 17 common differentially spliced genes. Only 3 genes were differentially responsive to hypoxia at the gene (>2.0) and AS levels in both cell types. Functional assignments revealed unique profiles of gene expression with complex regulation of differentiation, extracellular matrix, intermediate filament and metabolic marker genes. Antioxidant genes, striated muscle genes and insulin/IGF-1 signaling intermediates were down-regulated. There was a coordinate induction of 9 out of 12 acidic keratins that along with other epithelial and cell adhesion markers implies a partial mesenchymal to epithelial transition.ConclusionsWe conclude that severe hypoxia confers a quiescent phenotype in hMSCs that is reflected by both the transcriptome profile and gene-specific changes of splicosome actions. The results reveal that severe hypoxia imposes markedly different patterns of gene regulation of MSCs compared with more moderate hypoxia. This is the first study to report hypoxia-regulation of AS in stem/progenitor cells and the first molecular genetic characterization of MSC in a hypoxia-induced quiescent immobile state.

show abstract

Section: Resultsmentioning

confidence: 99%

Severe hypoxia exerts parallel and cell-specific regulation of gene expression and alternative splicing in human mesenchymal stem cells

Shehadeh

et al. 2014

BMC Genomics

View full text Add to dashboard Cite

show abstract

“…Further, TP53 has been shown to modulate CDK4/RB1 through CDKN1A in human colon cancer cells [77]. TP53 can increase the expression of CDKN1A, which in turn decreases phosphorylation of RB1 [78]. Additionally, CDKN1A may also decrease phosphorylation of RB1 via CDK2-Cyclin D1 complex [79].…”

Section: Resultsmentioning

confidence: 99%

Imprinted Genes and the Environment: Links to the Toxic Metals Arsenic, Cadmium and Lead

Smeester

Yosim

Nye

et al. 2014

Genes

View full text Add to dashboard Cite

Imprinted genes defy rules of Mendelian genetics with their expression tied to the parent from whom each allele was inherited. They are known to play a role in various diseases/disorders including fetal growth disruption, lower birth weight, obesity, and cancer. There is increasing interest in understanding their influence on environmentally-induced disease. The environment can be thought of broadly as including chemicals present in air, water and soil, as well as food. According to the Agency for Toxic Substances and Disease Registry (ATSDR), some of the highest ranking environmental chemicals of concern include metals/metalloids such as arsenic, cadmium, and lead. The complex relationships between toxic metal exposure, imprinted gene regulation/expression and health outcomes are understudied. Herein we examine trends in imprinted gene biology, including an assessment of the imprinted genes and their known functional roles in the cell, particularly as they relate to toxic metals exposure and disease. The data highlight that many of the imprinted genes have known associations to developmental diseases and are enriched for their role in the TP53 and AhR pathways. Assessment of the promoter regions of the imprinted genes resulted in the identification of an enrichment of binding sites for two transcription factor families, namely the zinc finger family II and PLAG transcription factors. Taken together these data contribute insight into the complex relationships between toxic metals in the environment and imprinted gene biology.

show abstract

“…A distinct role for TGF-β and activin in erythropoiesis has been reported in studies of primary and transformed cells [16-28,30-32,36,49,50]. However, given the many stages of erythropoiesis from the stem cell quiescence to red cell enucleation and the many cytokines involved, these studies cannot be fully informative about the context in which signaling networks co-mediate TGF-β/activin effects [8,9].…”

Section: Discussionmentioning

confidence: 99%

“…TGF-β and activin both regulate different cellular events of hematopoiesis in a lineage specific manner [26-28]. Both cytokines stimulate erythroid differentiation, accompanied by hemoglobin synthesis, and TGF-β inhibited growth of early but not late erythroid progenitor cells [26,29-32].…”

Section: Introductionmentioning

confidence: 99%

Crosstalk between the Smad and the Mitogen-Activated Protein Kinase Pathways is Essential for Erythroid Differentiation of Erythroleukemia Cells Induced by TGF-β, Activin, Hydroxyurea and Butyrate

Akel

Bertolette

Ruscetti

2013

J Leuk

View full text Add to dashboard Cite

The role of crosstalk between the Smad and the MAPK signaling pathways in activin-, transforming growth factor-β (TGF-β)-, hydroxyurea (HU) - and butyrate-dependent erythroid differentiation of K562 leukemic cells was studied. Treatment with all four inducers caused transient phosphorylation of Smad2/3 and MAPK proteins including ERK, p38 and JNK. Use of specific inhibitors of p38, ERK and JNK MAPK proteins, and TGF-β type I receptor indicated that differentiation induced by each of these agents involves activation of Smad2/3 and p38 MAPK, and inhibition of ERK MAPK. Also, treatment of cells with an inhibitor of protein serine/threonine phosphatase, okadaic acid (OA), induced phosphorylation of Smad2/3, and p38 MAPK, coincident with its induction of erythroid differentiation. Specific inhibition of TGF-β type I receptor kinase activity not only abolished TGF-β/activin effects but also prevented Smad2/3 activation and erythroid differentiation induced by OA, HU and butyrate. The TGF-β type I receptor kinase inhibitor blocked OA-induced differentiation but not p38 MAPK phosphorylation demonstrating that signals from both pathways are needed. As previously observed, addition of ERK1/2 MAPK inhibitors upregulated Smad2/3 phosphorylation and enhanced differentiation, but these effects were dependent on signals from the TGF-β type I receptor. These data indicate that activation of both Smad2/3 and p38 MAPK signaling pathways is a prerequisite to induce erythroid differentiation of erythroleukemia cells by activin, TGF-β, HU, OA and butyrate.

show abstract

The Role of Activin A in Regulation of Hemopoiesis

Cited by 62 publications

References 79 publications

Severe hypoxia exerts parallel and cell-specific regulation of gene expression and alternative splicing in human mesenchymal stem cells

Severe hypoxia exerts parallel and cell-specific regulation of gene expression and alternative splicing in human mesenchymal stem cells

Imprinted Genes and the Environment: Links to the Toxic Metals Arsenic, Cadmium and Lead

Crosstalk between the Smad and the Mitogen-Activated Protein Kinase Pathways is Essential for Erythroid Differentiation of Erythroleukemia Cells Induced by TGF-β, Activin, Hydroxyurea and Butyrate

Contact Info

Product

Resources

About