Project description:Coordination of a complex series of transcriptional, structural and signaling events culminates in cellular senescence, a crucial tumor suppressor mechanism. We have discovered a repressor complex composed of TBX3 and CAPERa which functions upstream of the RB and p53 effector pathways and is required to prevent senescence of primary cells and in mouse embryos. TBX3/ CAPERa directly binds and represses transcription and chromatin structure of genes in multiple senescence pathways and the LncRNA UCA1, which we have identified as a novel tumor suppressor. The TBX3/ CAPERa complex is physically disrupted in oncogene induced senescence, providing a new molecular mechanism for derepression of prosenescence pathways in this system. Our results provide new insight into the oncogenic properties of TBX3, and are the first demonstration of CAPERa and UCA1 function in vivo. mRNA Seq based gene differential expression analysis of two sample types (TBX3, Caper) relative to control and two sample types (pCDNA3.1, UCA1) relative to each other.
Project description:Coordination of a complex series of transcriptional, structural and signaling events culminates in cellular senescence, a crucial tumor suppressor mechanism. We have discovered a repressor complex composed of TBX3 and CAPERa which functions upstream of the RB and p53 effector pathways and is required to prevent senescence of primary cells and in mouse embryos. TBX3/ CAPERa directly binds and represses transcription and chromatin structure of genes in multiple senescence pathways and the LncRNA UCA1, which we have identified as a novel tumor suppressor. The TBX3/ CAPERa complex is physically disrupted in oncogene induced senescence, providing a new molecular mechanism for derepression of prosenescence pathways in this system. Our results provide new insight into the oncogenic properties of TBX3, and are the first demonstration of CAPERa and UCA1 function in vivo.
Project description:LncRNA urothelial carcinoma-associated 1 (UCA1) is an oncogene in breast cancer. Previous reports indicates that lncRNAs may function as competing endogenous RNAs (ceRNAs) to sponge miRNAs, thereby modulating the derepression of miRNA targets. To characterize microRNAs that associated with UCA1, the microRNAs associated with UCA1 were extracted from the UCA1-MS2 RNP complexes and analyzed by miRNA-seq.
Project description:Photoperiodic floral initiation in the leaf is controlled by the hub gene CONSTANS (CO) while jasmonates (JAs) control flower senescence. Although both processes are chronologically ordered, no association between them has been described to date. We show that CO protein remains in Arabidopsis flowers after the floral induction, although displaying a different tissue and diurnal pattern than in leaves. We found that changes in CO expression alter flower senescence and abscission by interfering with the JA response, supported by petal specific analysis as well as CO overexpression in JA synthesis and signaling mutants. CO has a ZIM-like domain that mediates interaction with the JA response repressor JAZ3 (jasmonate ZIM-domain 3), inhibiting its repressor activity and activating downstream transcription factors involved in flower senescence. The complex CO-JAZ3 also interacts with the E3 ubiquitin ligase Coronatine Insensitive 1 (COI1) leading to its degradation in the presence of jasmonates. Therefore, the coordinated recruitment of photoperiodic and jasmonate signaling pathways would be an efficient way for plants to chronologically order the floral process and ensure the success of offspring production.
Project description:Oncogene-induced senescence provides a barrier against malignant transformation. Senescent cells secrete pro-inflammatory cytokines, chemokines and growth factors collectively known as the senescence-associated secretory phenotype (SASP). Paradoxically, the SASP can also negatively impact the neighbouring tissues through inducing an inflammatory environment that promotes tumorigenesis and aged-related pathologies. We have previously shown that the lncRNA MIR31HG is overexpressed and located in the cytoplasm during BRAF-induced senescence. In young proliferating cells, nuclear MIR31HG inhibits p16/CDKN2A expression through interaction with polycomb repressor complexes (PRC1/2). Here, we show that MIR31HG regulates the expression and secretion of a subset of SASP components during BRAF-induced senescence. The SASP secreted from senescent cells depleted for MIR31HG fails to induce paracrine invasion without affecting the growth inhibitory effect. Mechanistically, MIR31HG interacts with the translation factor YBX1 facilitating its phosphorylation at serine 102 (p-YBX1S102) by the kinase RSK. p-YBX1S102 induces IL1A translation which acts as upstream regulator inducing the transcription of the other SASP mRNAs. Our results suggest a dual role for MIR31HG in senescence depending on its cellular localization and place the lncRNA as a potential therapeutic target in the treatment of senescence-related pathologies.
Project description:Inhibition of UCA1 by siRNAs sensitizes the chemoresistant ovarian cancer cell line OAW42-R to the effect of cisplatin We therefore studied the transcriptomic consequences of UCA1 downregulaiton in order to asses the mechanisms and pathways by which regulation the downregulaiton of UCA1 affects cell's response to cisplatin
Project description:Purpose: to evaluate changes in the expression of microRNAs, which contribute to explain a phenotype of differential pigmentation and reduction of proliferation, in B16F1 melanoma cells exposed to analogue of tymidine BrdU or aminoacid L-Tyr Methods: Small RNAseq evaluation of the expression profiles of miRNAs in B16F1 melanoma cells exposed to BrdU (0.25 μg / mL) and L-Tyr (5 mM) for 72 h, as well as the expression by RT-qPCR of some molecular targets related with melanogenesis, cell cycle and senescence and construction of network models of regulation and co-expression of microRNAs. Results: It was confirmed that stimulation or melanogenic repression with L-Tyr or BrdU, respectively, generates changes in melanin concentration, reduction in proliferation and changes in expression of microRNAs 470-3p, 470-5p, 30d-5p , 129-5p, 148b-3p, 27b-3p and 211-5p, which presented patterns of coordinated co-expression, related to melanogenesis through their putative targets MITF, Tyr and Tyrp1 and control of cell cycle and senescence: Cyclin D1, Cdk2, Cdk4 and p21. Conclusion: This work improves our understanding of the events of melanogenesis, cell cycle control, and senescence mediated by the coordinated expression of miRNAs and helps to develop new approaches to a molecular biology of melanoma that operates in network
Project description:Transcriptional profiling of human mesenchymal stem cells comparing normoxic MSCs cells with hypoxic MSCs cells. Hypoxia may inhibit senescence of MSCs during expansion. Goal was to determine the effects of hypoxia on global MSCs gene expression.