| Gene name: | BRAF |
| Aging type: | Accelerate |
| Aging characteristic: |
| Tissue type: | -- |
| Cell name: | HPCs,LCH cells |
| Gene ID: | 673 |
| Category: | protein coding |
| Phenotype: | Langerhans cell histiocytosis |
| Experimental category: | HL |
| PMID: | 33958797 |
| Experiment: | RT-PCR//SA-β-gal activity assay//ELISA//Immunofluorescence//RNA-seq |
| Description: | HPCs isolated from BRAF-V600EScl+ mice were positive for SAβGal; and pro- duced SASP-associated proteins, all features consistent with a senescent state. LCH cells isolated from peripheral tissues of BRAF-V600EScl+ mice were also in a senescent state, as shown by reduced Ki-67 expression, expression of Cdkn2a, SAβGal activity and the production of SASP-associated proteins.Human BRAFV600E-transduced HPCs exhibited canonical markers of cellular senescence, including enlarged cellular size, positivity for SAβGal staining, senescence-associated heterochromatin foci and increased production of SASP cytokines. Gene expression profiling of transduced human BRAF-V600E+GFP+ HPCs confirmed the senescence signature16 and LCH lesions that formed in humanized mice reconstituted with human BRAFV600E CD34+ cells also had increased SAβGal activity and high p16INK4a levels.CD34+ BM cells isolated from patients with LCH also expressed a senescence signature, including increased expression of CDKN2A, CDKN2C, CDKN2D, CD9, MDM2 and genes encoding matrix metalloproteinases. |
| Regulatory pathway: | MTOR |
| R-AG-Pathway: | Activation |
| Official symbol(s): | MTOR |
| Pathway experiment: | ELISA//Flow cytometry |
| Pathway description: | We first confirmed that inhibition of the mTOR pathway was sufficient to reduce the production of inflammatory cytokines by BRAF-V600E+ senescent HPCs in vitro. And in line with our hypothesis, SASP inhibition significantly reduced BRAF-V600E+ HPC skewing into MNPs in vitro. Rapamycin treatment also partially reduced excess MNP differen- tiation from BRAF-V600E GFP HPCs co-cultured with senescent BRAF-V600E+GFP+ HPCs, further establishing that mTOR inhi- bition reduced the release of SASP-associated molecules driving HPC-sustained MNP differentiation potential. |
Annotation:
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