FL5.12 Bfl-1DC/p53DD-derived splenic tumors compared to the parental FL5.12 Bfl-1DC/p53DD cell line

ABSTRACT: The antiapoptotic Bcl-2 family member Bfl-1 is upregulated in many human tumors in which NF-kB is implicated, and contributes significantly to tumor cell survival and chemoresistance. We previously found that NF-kB induces transcription of bfl-1, and that the Bfl-1 protein is also regulated by the ubiquitin-proteasome. However little is known of the role that dysregulation of Bfl-1 turnover plays in cancer. We found that ubiquitination-resistant mutants of Bfl-1 display increased stability and greatly accelerate tumor formation in a mouse model of leukemia/lymphoma. Gene expression profiling revealed that tyrosine kinase Lck is highly upregulated and activated in these tumors compared to the parental cells, as were several genes in the RANK signaling pathway, and leads to activation of the IKK, Akt and Erk signaling pathways, which are key mediators in cancer. Tumor assays with cells coexpressing constitutively active Lck with Bfl-1, or with tumor-derived cells following shRNA-mediated Lck knockdown, unveiled functional cooperation between Bfl-1 and Lck in leukemia/lymphomagenesis. These data demonstrate that ubiquitination is a critical mechanism for regulating Bfl-1 function, and suggest that mutations in bfl-1 or in the signaling pathways that control its ubiquitination may predispose to cancer. Additionally since bfl-1 is upregulated in many human hematopoietic tumors, these data suggest that strategies to promote Bfl-1 ubiquitination may improve therapy in drug-resistant tumors. FL5.12 pro-B cells were stably transfected with Bfl-1DC and p53DD (Parental - P) and injected i.v. into nude mice. The spleens were harvested from three independent mice that developed leukemia/lymphoma (T1, T2, and T3). To identify the changes in gene expression that occurred during tumorigenesis, RNA was isolated from the parental cell line (P) and from three independent splenic tumors (T) and hybridized to Affymetrix Mouse Genome 430A_2.0 arrays. The analysis was performed in duplicate.

ORGANISM(S): Mus musculus

SUBMITTER: Jérôme Kucharczak 

PROVIDER: E-GEOD-18204 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress