New Players from Genomic-Scale Screens

Science's STKE  21 Oct 2003:
Vol. 2003, Issue 205, pp. tw414-TW414
DOI: 10.1126/stke.2003.205.tw414

The availability of large collections of cDNAs to human genes has enabled genome-scale screens for new components of signaling pathways. Iourgenko et al. transfected cells with each of some 20,000 full-length cDNAs. They then monitored the cells for increased expression of a reporter gene linked to the interleukin 8 (IL-8) promoter. Although not previously implicated in regulation of IL-8, cyclic AMP response element-binding (CREB) proteins were found to be strong activators of the IL-8 reporter. The screen also identified TORC1 [for transducer of regulated CREB]. TORC1 is a member of a family of evolutionarily conserved, previously uncharacterized proteins that appears to function as coactivator proteins with CREB. Chanda et al. conducted a similar screen for genes whose expression would activate AP-1 (activator protein-1). Although AP-1-mediated transcription has been highly studied as a key component of growth and mitogenic response pathways, new regulators were identified along with known ones in the screen. Because such transient expression might produce nonphysiological outcomes, the authors further analyzed candidate genes by other methods, including elimination of the potential modulators by expression of short hairpin RNA. The latter manipulation inhibited activation of AP-1 promoters in response to mitogenic stimuli in cultured human embryonic kidney cells. The authors propose that their combination of "integrative genomics approaches will allow for increasingly sophisticated models that extend our knowledge of the complex relationships between gene products, signal transduction pathways, and their underlying biological functions."

V. Iourgenko, W. Zhang, C. Mickanin, I. Daly, C. Jiang, J. M. Hexham, A. P. Orth, L. Miraglia, J. Meltzer, D. Garza, G.-W. Chirn, E. McWhinnie, D. Cohen, J. Skelton, R. Terry, Y. Yu, D. Bodian, F. P. Buxton, J. Zhu, C. Song, M. A. Labow, Identification of a family of cAMP response element-binding protein coactivators by genome-scale functional analysis in mammalian cells. Proc. Natl. Acad. Sci. U.S.A. 100, 12147-12152 (2003). [Abstract] [Full Text]

S. K. Chanda, S. White, A. P. Orth, R. Reisdorph, L. Miraglia, R. S. Thomas, P. DeJesus, D. E. Mason, Q. Huang, R. Vega, D.-H. Yu, C. G. Nelson, B. M. Smith, R. Terry, A. S. Linford, Y. Yu, G. Chirn, C. Song, M. A. Labow, D. Cohen, F. J. King, E. C. Peters, P. G. Schultz, P. K. Vogt, J. B. Hogenesch, J. S. Caldwell, Genome-scale functional profiling of the mammalian AP-1 signaling pathway. Proc. Natl. Acad. Sci. U.S.A. 100, 12153-12158 (2003). [Abstract] [Full Text]