Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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FANCD2 Activates Transcription of TAp63 and Suppresses Tumorigenesis

ABSTRACT: Fanconi Anemia (FA) is a rare genetic disorder characterized by an increased susceptibility to squamous cell cancers. Fifteen FA genes are known, and the encoded proteins cooperate in a common DNA repair pathway. A critical step is the monoubiquitination of the FANCD2 protein, and cells from most FA patients are deficient in this step. How monoubiquitinated FANCD2 suppresses squamous cell cancers is unknown. Here we show that Fancd2-deficient mice are prone to Ras oncogene-driven skin carcinogenesis, while Usp1-deficient mice, expressing elevated cellular levels of Fancd2-Ub, are resistant to skin tumors. Moreover, Fancd2-Ub activates the transcription of the tumor suppressor TAp63, thereby promoting cellular senescence and blocking skin tumorigenesis. For FA patients, the reduction of FANCD2-Ub and TAp63 protein levels may account for their susceptibility to squamous cell neoplasia. Taken together, Usp1 inhibition may be a useful strategy for upregulating TAp63 and preventing or treating squamous cell cancers in the general non-FA population. Examination of FANCD2 binding after UV treatment in 293T cells

ORGANISM(S): Homo sapiens

SUBMITTER: eunmi Park

PROVIDER: E-GEOD-46902 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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FANCD2 activates transcription of TAp63 and suppresses tumorigenesis.

Park Eunmi E Kim Hyungjin H Kim Jung Min JM Primack Benjamin B Vidal-Cardenas Sofia S Xu Ye Y Price Brendan D BD Mills Alea A AA D'Andrea Alan D AD

Molecular cell 20130601 6

Fanconi anemia (FA) is a rare genetic disorder characterized by an increased susceptibility to squamous cell cancers. Fifteen FA genes are known, and the encoded proteins cooperate in a common DNA repair pathway. A critical step is the monoubiquitination of the FANCD2 protein, and cells from most FA patients are deficient in this step. How monoubiquitinated FANCD2 suppresses squamous cell cancers is unknown. Here we show that Fancd2-deficient mice are prone to Ras-oncogene-driven skin carcinogen ...[more]

PMID: 23806336

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Project description:Fanconi anemia (FA) is a genetic disorder characterized by congenital abnormalities, bone marrow failure and increased susceptibility to cancer. Of the fifteen FA proteins, Fanconi anemia group C (FANCC) is one of eight FA core complex components of the FA pathway. Unlike other FA core complex proteins, FANCC is mainly localized in the cytoplasm, where it is thought to function in apoptosis, redox regulation, cytokine signaling and other processes. Previously, we showed that regulation of FANCC involved proteolytic processing during apoptosis. To elucidate the biological significance of this proteolytic modification, we searched for molecular interacting partners of proteolytic FANCC fragments. Among the candidates obtained, the transcriptional corepressor protein C-terminal binding protein-1 (CtBP1) interacted directly with FANCC and other FA core complex proteins. Although not required for stability of the FA core complex or ubiquitin ligase activity, CtBP1 is essential for proliferation, cell survival and maintenance of chromosomal integrity. Expression profiling of CtBP1-depleted and FA-depleted cells revealed that several genes were commonly up- and down-regulated, including the Wnt antagonist Dickkopf-1 (DKK1). These findings suggest that FA and Wnt signaling via CtBP1 could share common effectors. HeLa cell line was grown in DMEM media supplemented with 10% FBS and were incubated in 5% CO2 at 37Â°C. A four-plasmid (pRSV-Rev, pMDLg/pRRE, pMD2.G and pLKO.1) expression system was used for lentiviral production. Different pLKO.1 plasmids carrying shRNAs targeting FANCA, FANCD2, CtBP1 or CtBP2 or a lentiviral control vector pLKO.1-scrambled were used. Lentiviral particles were produced via calcium phosphate-mediated transient transfection of the four plasmids into HEK293T cells. Cells were exposed to appropriate lentiviral particles. In each experiment, HeLa cells were transduced for 6 hours with filtered supernatant containing recombinant lentiviral particles. After transduction, the cells were cultured for 72 hours. Total RNA extracts from 3 different samples of each scrambled, CtBPs and FANCD2 shRNA treated HeLa cells were subjected to gene expression profiling via microarray analysis. Gene expression profiles were determined with Affymetrix GeneChipÂ® Human Gene 1.0.

Project description:The RUNX genes encode for transcription factors involved in development and human disease. RUNX1 and RUNX3 are frequently associated with leukemias, yet the basis for their involvement in leukemogenesis is not fully understood. Here we show that Runx1;Runx3 double knockout (DKO) mice exhibited lethal phenotypes due to bone marrow failure and myeloproliferative disorder. These contradictory clinical manifestations are reminiscent of human inherited bone marrow failure syndromes like Fanconi anemia (FA), caused by defective DNA repair. Indeed, Runx1;Runx3 DKO cells showed mitomycin C hypersensitivity, due to impairment of monoubiquitinated-FANCD2 recruitment to DNA damage foci, although FANCD2 monoubiquitination in the FA pathway was unaffected. RUNX1 and RUNX3 interact with FANCD2 independent of CBFM-NM-2, suggesting non-transcriptional role for RUNX in DNA repair. These findings suggest that RUNX dysfunction causes DNA repair defect, besides transcriptional misregulation, and promotes development of leukemias and other cancers. 6 mice were analyzed in this study. 3 Runx1;Runx3 double knockout cKit+Sca1+Lin- hematopoietic stem/progenitor cells were compared with their wild type littermate controls. RNA was isolated from 3 independent Runx1;Runx3 WT KSL samples, each pooled from 3 Runx1;Runx3 WT mice, and 3 independent Runx1;Runx3 DKO KSL samples, using the RNeasy Micro Kit (QIAgen). RNA integrity and quantity was assessed using the Agilent 2000 Bioanalyzer system. 3 M-NM-<g to 5 M-NM-<g RNA was processed using WT-Ovation Pico RNA Amplification System (NuGEN) paired with the WT-Ovation Exon Module and FL-Ovation cDNA Biotin Module (NuGEN). A detailed protocol in the userM-bM-^@M-^Ys guide kit was used without modification. cDNA were prepared for hybridization on GeneChip Mouse Gene 1.0 ST Arrays (Affymetrix) according to the instructions in GeneChip Hybridization Wash and Stain Kit for ST arrays (Affymetrix). Microarray hybridization, scanning and preliminary MAS 5.0 normalizations were completed at the A*STAR Biopolis Shared Facilities (BSF).

Dataset Information

FANCD2 Activates Transcription of TAp63 and Suppresses Tumorigenesis

Publications

FANCD2 activates transcription of TAp63 and suppresses tumorigenesis.

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