Inhibition Of P53 In Cells Research Articles

FGFR2 mutations in bent bone dysplasia syndrome activate nucleolar stress and perturb cell fate determination.

Fibroblast Growth Factor (FGF) signaling promotes self-renewal in progenitor cells by encouraging proliferation and inhibiting cellular senescence. Yet, these beneficial effects can be hijacked by disease-causing mutations in FGF receptor (FGFR) during embryogenesis. By studying dominant FGFR2 mutations that are germline in bent bone dysplasia syndrome (BBDS), we reveal a mechanistic connection between FGFR2, ribosome biogenesis, and cellular stress that links cell fate determination to disease pathology. We previously showed that FGFR2 mutations in BBDS, which amplify nucleolar targeting of FGFR2, activate ribosomal DNA (rDNA) transcription and delay differentiation in osteoprogenitor cells and patient-derived bone. Here we find that the BBDS mutations augment the ability of FGFR2 to recruit histone-remodeling factors that epigenetically activate transcriptionally silent rDNA. Nucleolar morphology is controlled by chromatin structure, and the high levels of euchromatic rDNA induced by the BBDS mutations direct nucleolar disorganization, alter ribosome biogenesis, and activate the Rpl11-Mdm2-p53 nucleolar stress response pathway. Inhibition of p53 in cells expressing the FGFR2 mutations in BBDS rescues delayed osteoblast differentiation, suggesting that p53 activation is an essential pathogenic factor in, and potential therapeutic target for, BBDS. This work establishes rDNA as developmentally regulated loci that receive direct input from FGF signaling to balance self-renewal and cell fate determination.

Highly activated p53 contributes to selectively increased apoptosis of latently HIV-1 infected cells upon treatment of anticancer drugs.

BackgroundDespite the successful inhibition of human immunodeficiency virus type 1 (HIV-1) replication by combination antiretroviral therapy, cells latently infected with HIV-1 remaining in patients are a major obstacle for eradication of HIV-1 infection. The tumor suppressor factor p53 is activated by HIV-1 infection, and restricts HIV-1 replication. However, a therapeutic strategy based on p53 activity has not been considered for elimination of latently infected cells.MethodsApoptotic cells were analyzed using flow cytometry with anti-annexin A5-FITC Ab and PI staining upon treatment of anticancer drugs. The expression and activation of p53 and apoptotic molecules in latently HIV-1-infected T cells were compared using Western blot analysis. The role of p53 in the anticancer drug treatment-induced apoptosis of cells latently infected with HIV-1 was determined by knock-down experiment using siRNA against p53.ResultsUpon treatment with 5-fluorouracil (5-FU), apoptosis was increased in latently infected ACH2 cells encoding competent p53 compared with uninfected parent A3.01 cells, while the apoptosis of latently infected p53 null J1.1 cells was less than that of uninfected cells. Treatment with 5-FU increased the levels of cleaved caspase-3 and PARP in ACH2 cells compared with uninfected and latently infected p53 null J1.1 cells. The levels of expression and activation of p53 were higher in both latently infected ACH2 and NCHA2 cells than in uninfected cells. Furthermore, the activation levels of p53 in both cells were further increased upon 5-FU treatment. Consistent with p53 status, apoptosis was markedly increased in ACH2 and NCHA2 cells compared with uninfected and latently infected J1.1 cells upon treatment with other anticancer drugs such as doxorubicin and etoposide. Inhibition of p53 in cells with latent HIV-1 infection diminished apoptosis upon 5-FU treatment.ConclusionEvidence described here indicate that when treated with anticancer drugs, apoptosis of cells with latent HIV-1 infection was increased via the p53 activation pathway and may provide information for application of anticancer drugs to selectively eliminate HIV-1 reservoirs.