Murine Prostate Tissue: Rb1 null vs. Rb1 E2F binding deficient mutant
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE25615 | GEO | 2010/11/27
SECONDARY ACCESSION(S): PRJNA133957
REPOSITORIES: GEO
Similar Datasets
Project description:Transcriptional profilling of 60 day old prostate tissue from Rb1F/F:Trp53F/F:PB-Cre4 or Rb1R654W/F:Trp53F/F:PB-cre4 mice versus wild type prostate tissue. Profiles used to compare deregulation of known E2F target genes in prostate tissue expressing a mutant Rb1 gene to tissue lacking Rb1 expression. Tissue from two Rb1F/F:Trp53F/F:PB-Cre4 (null) mice or two Rb1654/F:Trp53F/F:PB-cre4 (mutant) mice compared to a pool of tissue from 3 wild type mice using two color arrays.
2010-11-27 | E-GEOD-25615 | biostudies-arrayexpress
Project description:Genomic loss of RB1 is a common alteration in castration-resistant prostate cancer (CRPC) and is associated with poor patient outcomes. RB1-loss is also a driver event that promotes the neuroendocrine transdifferentiation of prostate cancer (PCa). The loss of Rb protein disrupts the Rb-E2F repressor complex and thus hyperactivates E2F transcription activators. While the impact of RB1-loss on PCa progression and linage plasticity has been previously studied, the underline mechanisms remain unclear. Using an integrated cistromic and transcriptomic analysis, we have characterized Rb activities in multiple CRPC models by identifying Rb directly regulated genes and revealed that Rb has distinct binding sites and targets in TP53-mutated CRPC. Significantly, we show that RB1-loss promotes the noncanonical activator function of LSD1/KDM1A, which stabilizes chromatin binding of E2F1, and hence sensitizes CRPC tumor to the LSD1 inhibitor treatment. These results provide new molecular insights of Rb activity in PCa progression and suggest LSD1 as a potential therapeutic target in CRPC with RB1-loss.
2022-01-14 | GSE176402 | GEO
Project description:Genomic loss of RB1 is a common alteration in castration-resistant prostate cancer (CRPC) and is associated with poor patient outcomes. RB1-loss is also a driver event that promotes the neuroendocrine transdifferentiation of prostate cancer (PCa). The loss of Rb protein disrupts the Rb-E2F repressor complex and thus hyperactivates E2F transcription activators. While the impact of RB1-loss on PCa progression and linage plasticity has been previously studied, the underline mechanisms remain unclear. Using an integrated cistromic and transcriptomic analysis, we have characterized Rb activities in multiple CRPC models by identifying Rb directly regulated genes and revealed that Rb has distinct binding sites and targets in TP53-mutated CRPC. Significantly, we show that RB1-loss promotes the noncanonical activator function of LSD1/KDM1A, which stabilizes chromatin binding of E2F1, and hence sensitizes CRPC tumor to the LSD1 inhibitor treatment. These results provide new molecular insights of Rb activity in PCa progression and suggest LSD1 as a potential therapeutic target in CRPC with RB1-loss.
2022-01-14 | GSE176403 | GEO
Project description:Murine Prostate Tissue: Rb1 null vs. Rb1 E2F binding deficient mutant
| PRJNA133957 | ENA
Project description:The retinoblastoma protein (pRB) is best known for regulating cell proliferation through E2F transcription factors. In this report we investigate the properties of a targeted mutation that disrupts pRB interactions with the transactivation domain of E2Fs. Mice that carry this mutation endogenously (Rb1∆G) are defective in regulating E2F target genes. Surprisingly, cell cycle regulation in Rb1∆G/∆G MEFs strongly resembles that of wild type. In a serum deprivation induced cell cycle exit, Rb1∆G/∆G MEFs display a similar magnitude of E2F target gene derepression as Rb1-/-, even though Rb1∆G/∆G cells exit the cell cycle normally. Interestingly, cell cycle arrest in Rb1∆G/∆G MEFs is responsive to p16 expression, indicating that the ΔG-pRB protein can be activated in G1 to arrest proliferation through non-E2F mechanisms. Some Rb1∆G/∆G mice die neonatally with a muscle degeneration phenotype, while the others live a normal lifespan with no evidence of spontaneous tumor formation. Histological analysis reveals discrete examples of hyperplasia in the mammary epithelium, but most tissues appear normal while being accompanied by derepression of pRB regulated E2F targets. This suggests that non-E2F, pRB dependent pathways may have a more relevant role in proliferative control than previously identified.
2014-04-14 | GSE54924 | GEO
Project description:The efficacy of immunotherapy in prostate cancer is not satisfactory due to the “cold” tumor microenvironment and the paucity of neoantigens. The STING-TBK1-IRF3 signaling axis as core molecules of the innate immune system is increasingly recognized as a candidate target for cancer immunotherapy. Previou studies reported that CDK4/6 inhibitors induced DNA damage to activate the cGAS-STING pathway. However, the underlying mechanisms of how CDK4/6 inactivated the cGAS-STING pathway are still elusive. Here we revealed that treatment with CDK4/6 inhibitors enhance the anti-tumor effect of STING agonists in prostate cancer cells. Mechanically, CDK4/6 phosphorylated TBK1 at S527 to inactive the STING signaling pathway independent of RB1 in prostate cancer cell. Then, we also found that CDK4/6 phosphorylated RB1 at S249/T252 to induce the interaction of RB1 with TBK1 and diminish the phosphorylation of TBK1 at S172, which also suppresses the activation of the STING pathway. Collectively, we found that CDK4/6 inhibits the STING/TBK1/IRF3 axis through RB1-dependent and RB1-independent pathways in prostate cancer cells. These insights provide the novel evidence for CDK4/6 suppressing the innate immune response of prostate cancer.
2024-06-01 | GSE268848 | GEO
Project description:The efficacy of immunotherapy in prostate cancer is not satisfactory due to the heterogeneity of this cancer, the “cold” tumor microenvironment and the paucity of neoantigens. The STING-TBK1-IRF3 signaling axis as core molecules of the innate immune system is increasingly recognized as a candidate target for cancer immunotherapy. Inhibition of CDK4/6 has been reported to r increase T-cell activation to enhance antitumor immunity. However, little is known about the relationship between CDK4/6 and innate immune-related STING signaling. In this study, we revealed that combination treatment with CDK4/6 inhibitors and STING agonists is significantly more effective than treatment with STING agonists alone in eliminating prostate cancer cells. Then, we demonstrated that CDK4/6 phosphorylate TBK1 at S527 to inactive the STING signaling pathway independent of RB1 in prostate cancer cell. On the other hand, CDK4/6 phosphorylate RB1 at S249/T252 to promote the interaction of RB1 with TBK1 and diminish the phosphorylation of TBK1 at S172, which also suppresses the activation of the STING pathway. Collectively, we found that CDK4/6 inhibits the STING/TBK1/IRF3 axis through RB1-dependent and RB1-independent pathways and elucidated the detailed mechanism. These insights lay a solid foundation for the synergistic application of CDK4/6 inhibitors with STING activators in prostate cancer patients.
2024-05-21 | GSE248019 | GEO
Project description:The goal of this study was to perform transcriptomics on wildtype, PTEN single knockout (SKO) and PTEN;Rb1 double knockout (DKO) mouse prostate organoids. We isolated basal cells from PTEN floxed and PTEN;Rb1 floxed mouse prostates and infected with either RFP control or Cre recombinase to establish wildtype, SKO, and DKO mouse prostate organoids.
2023-09-01 | GSE221020 | GEO
Project description:Advances in genomic signatures have begun to dissect breast cancer heterogeneity, and application of these signatures will allow the prediction of which pathways are important in tumor development. Here we used genomic signatures to predict involvement of specific E2F transcription factors in Myc-induced tumors. We genetically tested this prediction by interbreeding Myc transgenics with mice lacking various activator E2F alleles. Tumor latency decreased in the E2F1 mutant background and significantly increased in both the E2F2 and E2F3 mutants. Investigating the mechanism behind these changes revealed a reduction in apoptosis in the E2F1 knockout strain. E2F2 and E2F3 mutant backgrounds alleviated Myc effects on the mammary gland, reducing the susceptible tumor target population. Gene expression data from tumors revealed that the E2F2 knockout background resulted in fewer tumors with EMT, corresponding with a reduction in probability of Ras activation. In human breast cancer we found that a low probability of E2F2 pathway activation was associated with increased relapse-free survival time. Together these data illustrate the predictive utility of genomic signatures in deciphering the heterogeneity within breast cancer and illustrate the unique genetic requirements for individual E2Fs in mediating tumorigenesis in both mouse models and human breast cancer. MMTV-Myc tumors were generated in an E2F wild-type, E2F1 null, E2F2 null and E2F3 heterozygous background. When the primary tumor reached the endpoint, the tumors were flash frozen. 20 tumors from each genotype were selected for microarray analysis.
2011-12-29 | E-GEOD-24594 | biostudies-arrayexpress
Project description:Human prostate cancer LNCaP cells infected with Lentivirus carried huamn BRCA2 gRNA alone or in combination with lentivirus carrying human RB1 shRNA. Infected cell were selcted by drug selection and the knockdown were confirm by westernblot or qPCR
2020-05-07 | GSE114153 | GEO