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Published online on September 26, 2003, 10.1073/pnas.1934839100

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Cell Biology
Genome-scale functional profiling of the mammalian AP-1 signaling pathway

Sumit K. Chanda *{dagger}, Suhaila White *{ddagger}, Anthony P. Orth *{ddagger}, Richard Reisdorph §, Loren Miraglia *, Russell S. Thomas ¶, Paul DeJesus *, Daniel E. Mason *, Qihong Huang §, Raquel Vega *, De-Hua Yu *, Christian G. Nelson *, Brendan M. Smith *, Robert Terry ||, Alicia S. Linford *, Yang Yu ||, Gung-wei Chirn ||, Chuanzheng Song ||, Mark A. Labow ||, Dalia Cohen ||, Frederick J. King *, Eric C. Peters *, Peter G. Schultz *, Peter K. Vogt §, John B. Hogenesch *, and Jeremy S. Caldwell *{dagger}

*Genomics Institute, Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121; Kalypsys, Incorporated, 11099 North Torrey Pines Road, La Jolla, CA 92037; §The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037; and ||Department of Functional Genomics, Novartis Institute for Biomedical Research, 100 Technology Square, Cambridge, MA 02139

Contributed by Peter K. Vogt, July 31, 2003

Large-scale functional genomics approaches are fundamental to the characterization of mammalian transcriptomes annotated by genome sequencing projects. Although current high-throughput strategies systematically survey either transcriptional or biochemical networks, analogous genome-scale investigations that analyze gene function in mammalian cells have yet to be fully realized. Through transient overexpression analysis, we describe the parallel interrogation of {approx}20,000 sequence annotated genes in cancer-related signaling pathways. For experimental validation of these genome data, we apply an integrative strategy to characterize previously unreported effectors of activator protein-1 (AP-1) mediated growth and mitogenic response pathways. These studies identify the ADP-ribosylation factor GTPase-activating protein Centaurin {alpha}1 and a Tudor domain-containing hypothetical protein as putative AP-1 regulatory oncogenes. These results provide insight into the composition of the AP-1 signaling machinery and validate this approach as a tractable platform for genome-wide functional analysis.

{dagger}To whom correspondence may be addressed.

{ddagger}S.W. and A.P.O. contributed equally to this work.

E-mail: chanda{at}gnf.org, caldwell{at}gnf.org.

www.pnas.org/cgi/doi/10.1073/pnas.1934839100
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