Elucidation of the physiologic role of TRIP-Br2 in cell cycle regulation and cancer pathogenesis

Abstract

The TRIP-Br/SERTAD family of mammalian transcriptional regulators has recently been cloned and shown to be involved in E2F-mediated cell cycle progression. We report, herein, further characterization of the least understood member of TRIP-Br/SERTAD family, TRIP-Br2 (also known as SEI-2 or SERTAD2). We assessed the role of TRIP-Br2 in development, transcriptional regulation and cell cycle progression by inactivating the TRIP-Br2 locus in mouse through insertional mutagenesis and exon trapping. Ablation of TRIP-Br2 did not lead to infertility, embryonic lethality or failure of lymphoid development in mice. Its overexpression, which was associated with the upregulation of E2F-mediated transcription, transformed NIH3T3 fibroblasts and promoted tumor growth in athymic nude mice. We performed high throughput expression profiling of TRIP-Br2 in multiple human tumor tissue arrays and showed that TRIP-Br2 is overexpressed in many human cancers. Apart from the identification and validation of TRIP-Br2 overexpression as a putative novel mechanism underlying human tumorigenesis, such as the case of hepatocellular carcinoma, we have also uncovered its potential as a novel chemotherapeutic drug target. As a proof-of-principle, we showed that the siRNA knockdown of TRIP-Br2 is sufficient to inhibit cell-autonomous growth of HCT-116 colorectal cancer cells in vitro. Lastly, we showed evidences that the oscillatory nature of TRIP-Br2 expression in cell cycle progression is tightly regulated by multiple mechanisms, including the ubiquitin-proteasome-dependent degradation pathway and the CRM1-mediated nuclear export pathway.