Ceapins are a new class of unfolded protein response inhibitors, selectively targeting the ATF6α branch.

The membrane-bound transcription factor ATF6α plays a cytoprotective role in the unfolded protein response (UPR), required for cells to survive ER stress. Activation of ATF6α promotes cell survival in cancer models. We used cell-based screens to discover and develop Ceapins, a class of pyrazole amides, that block ATF6α signaling in response to ER stress. Ceapins sensitize cells to ER stress without impacting viability of unstressed cells. Ceapins are highly specific inhibitors of ATF6α signaling, not affecting signaling through the other branches of the UPR, or proteolytic processing of its close homolog ATF6ß or SREBP (a cholesterol-regulated transcription factor), both activated by the same proteases. Ceapins are first-in-class inhibitors that can be used to explore both the mechanism of activation of ATF6α and its role in pathological settings. The discovery of Ceapins now enables pharmacological modulation all three UPR branches either singly or in combination.

Characterization of a human cell line stably over-expressing the candidate oncogene, dual specificity phosphatase 12.

BACKGROUND: Analysis of chromosomal rearrangements within primary tumors has been influential in the identification of novel oncogenes. Identification of the "driver" gene(s) within cancer-derived amplicons is, however, hampered by the fact that most amplicons contain many gene products. Amplification of 1q21-1q23 is strongly associated with liposarcomas and microarray-based comparative genomic hybridization narrowed down the likely candidate oncogenes to two: the activating transcription factor 6 (atf6) and the dual specificity phosphatase 12 (dusp12). While atf6 is an established transcriptional regulator of the unfolded protein response, the potential role of dusp12 in cancer remains uncharacterized. METHODOLOGY/PRINCIPAL FINDINGS: To evaluate the oncogenic potential of dusp12, we established stable cell lines that ectopically over-express dusp12 in isolation and determined whether this cell line acquired properties frequently associated with transformed cells. Here, we demonstrate that cells over-expressing dusp12 display increased cell motility and resistance to apoptosis. Additionally, over-expression of dusp12 promoted increased expression of the c-met proto-oncogene and the collagen and laminin receptor intergrin alpha 1 (itga1) which is implicated in metastasis. SIGNIFICANCE: Collectively, these results suggest that dusp12 is oncologically relevant and exposes a potential association between dusp12 and established oncogenes that could be therapeutically targeted.

The Autographa californica M nucleopolyhedrovirus fibroblast growth factor accelerates host mortality.

The fibroblast growth factor (vfgf) gene encoded by Autographa californica M nucleopolyhedrovirus (AcMNPV) has been shown to share functional properties with cellular fgfs; it is a secreted protein, binds heparin, and stimulates motility of insect cells. We previously reported that viruses containing or lacking vfgf produced similar yields of budded virus and had similar kinetics of viral DNA and protein syntheses in cultured cells. In this study, we characterized these viruses in two permissive hosts, Spodoptera frugiperda and Trichoplusia ni, using two insect developmental stages and two infection routes, by feeding and intrahemocoelic injection. In addition, we constructed an AcMNPV bacmid overexpressing vfgf under polyhedrin promoter control and characterized it in both cell culture and insects. Deletion of vfgf had no effect on the infectivity of AcMNPV. However, lack of vfgf delayed the time of death in two host species when the virus was delivered by feeding but not by intrahemocoelic injection. The virus overexpressing vfgf produced less budded virus than the control virus in cultured cells. In insect bioassays, the infectivity of this virus was greater than that of the parental virus in both insect species and significantly accelerated time of death of both hosts tested. Our results suggest that the AcMNPV vfgf may play a role in dissemination of virus infection from the midgut in the insect species tested.