title: Coordinate regulation of Fanconi anemia gene expression occurs through the Rb/E2F pathway.
abstract: Fanconi anemia (FA) is a genome instability syndrome that is characterized by progressive bone marrow failure and a high risk of cancer. FA patients are particularly susceptible to leukemia as well as squamous cell carcinomas (SCCs) of the head and neck, anogenital region and skin. Thirteen complementation groups and the corresponding FA genes have been identified, and their protein products assemble into nuclear core complexes during DNA-damage responses. Much progress has been made in our understanding of post-translational FA protein modifications and physical interactions. By contrast, little is known about the control of protein availability at the level of transcription. We report here that multiple FA proteins were downregulated during the proliferative arrest of primary human keratinocytes and HeLa cells, and that the observed regulation was at a transcriptional level. Proliferative stimuli such as expression of HPV16 E7 as well as E2F1 overexpression in primary cells resulted in coordinate FA upregulation. To define the underlying mechanism, we examined the endogenous FANCD2 promoter, and detected regulated binding of members of the E2F/Rb family in chromatin immunoprecipitation assays. Finally, a 1 kb promoter fragment was sufficient to confer E2F/Rb regulation in reporter assays. Taken together, our data demonstrate FA gene co-regulation in synchrony with the cell cycle and suggest that deregulated expression of individual FA genes-in addition to FA gene mutation-may promote FA-related human cancer.
authors.affiliation: 1Division of Hematology/Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: E E
authors.initials: EE
authors.lastname: Hoskins
authors.forename: R W
authors.initials: RW
authors.lastname: Gunawardena
authors.forename: K B
authors.initials: KB
authors.lastname: Habash
authors.forename: T M
authors.initials: TM
authors.lastname: Wise-Draper
authors.forename: M
authors.initials: M
authors.lastname: Jansen
authors.forename: E S
authors.initials: ES
authors.lastname: Knudsen
authors.forename: S I
authors.initials: SI
authors.lastname: Wells
mesh_terms: D050684:E2F Transcription Factors / Q000378:metabolism*; D005199:Fanconi Anemia / Q000235:genetics*; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D016161:Genes, Retinoblastoma; D006367:HeLa Cells; D006801:Humans; D011401:Promoter Regions, Genetic
chemical_list: D050684:E2F Transcription Factors; D051856:Fanconi Anemia Complementation Group Proteins