Project description:E2F-transcription factors activate many genes involved in cell cycle progression, DNA repair, and apoptosis. Hence, E2F-dependent transcription must be tightly regulated to prevent tumorigenesis, and therefore metazoan cells possess multiple E2F regulation mechanism. The best-known is the Retinoblastoma protein (RB), which is mutated in many cancers. Atypical E2Fs (E2F7 and -8) can repress E2F-target gene expression independently of RB and are rarely mutated in cancer. Therefore, they may act as emergency brakes in RB-mutated cells to suppress tumor growth. Currently it is unknown if and how RB and atypical E2Fs functionally interact in vivo. Here, we demonstrate that mice with liver-specific combinatorial deletion of Rb and E2f7/8 have reduced life spans compared to E2f7/8 or Rb deletion alone. This was associated with increased proliferation and enhanced malignant progression of liver tumors. Hence, atypical repressor E2Fs and RB cooperatively act as tumor suppressors in hepatocytes. We propose that the complex interactions between atypical E2Fs and RB on maintenance of genetic stability underlie this context-dependency.
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.
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.
Project description:To examine the role of Rb1 in gastrointestinal (GI) tumors we generated mice with an Apc1638N allele, Rbtm2brn floxed alleles, and a villlin-cre transgene (RBVCA). These mice had reduced median survival due to an increase in tumor incidence and multiplicity in the cecum and the proximal colon; they differed from murine intestinal tumors of the Apc1638N type which normally arise solely in the small intestine. We have examined by micro-array analysis three cecal tumors from these mice (probable adenomas), and compared them to three duodenal tumors (probable adenocarcinomas). Expression profiles of duodenal and cecal tumors relative to each other show unique gene subsets up and down regulated. The two tumor types were subsequently shown to differentially regulate distinct sets of genes over expressed in a majority of human colorectal carcinomas. Experiment Overall Design: We have compared 3 cecal tumors with 3 duodenal tumors from Rb1 deficient Apc1638N mice.
Project description:We used novel genetically engineered mouse models to investigate the role of HELLS during tumorigenesis. Loss of HELLS drastically decreased the incidence of retinoblastoma, delayed tumor progression, and increased overall survival. Tumors from Rb1/p107 DKO and Rb1/p107/Hells TKO mice were analyzed for gene expression using RNA-seq.
Project description:Zebrafish wildtype adult brain and rb1-embryonal brain tumor transcriptomes were used to identify candidate rb1-interacting chromatin remodelers and epigenetic regulators altered in rb1- transformed brain tumor cells. The data was also used for comparative analysis with zebrafish rb1-/- mutant transcriptome, to identify molecular pathways that distinguish transformed rb1- tumor cells from non-transformed rb1-/- mutant cells.
Project description:RB transcriptional corepressor 1 (RB1) is frequently mutated in human cancers, we discover a new target of oncogenic stress in RB1-mutant cells.
Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are deadly sarcomas that lack effective therapies. In most MPNSTs, the retinoblastoma (RB1) tumor suppressor is disabled by hyperactivation of cyclin dependent kinases (CDKs), commonly through loss of CDK inhibitory proteins such as p27(Kip1). RABL6A is an inhibitor of RB1 whose role in MPNSTs is unknown. To gain insight into MPNST development and establish new treatment options, we investigated RABL6A-RB1 signaling and CDK inhibitor-based therapy in MPNSTs.
Project description:To examine the role of Rb1 in gastrointestinal (GI) tumors we generated mice with an Apc1638N allele, Rbtm2brn floxed alleles, and a villlin-cre transgene (RBVCA). These mice had reduced median survival due to an increase in tumor incidence and multiplicity in the cecum and the proximal colon; they differed from murine intestinal tumors of the Apc1638N type which normally arise solely in the small intestine. We have examined by micro-array analysis three cecal tumors from these mice (probable adenomas), and compared them to three duodenal tumors (probable adenocarcinomas). Expression profiles of duodenal and cecal tumors relative to each other show unique gene subsets up and down regulated. The two tumor types were subsequently shown to differentially regulate distinct sets of genes over expressed in a majority of human colorectal carcinomas.