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PNAS 100 (21): 12153-12158

Copyright © 2003 by the National Academy of Sciences.

From the Cover


BIOLOGICAL SCIENCES / 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

Abstract: 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 α1 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. E-mail: chanda{at}gnf.org or caldwell{at}gnf.org.

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

Abbreviations: AP-1, activator protein 1; PMA, phorbol 12-myristate 13-acetate; GFAcT, genome functionalization through arrayed cDNA transduction; siRNA, small inhibitor RNA; shRNA, short hairpin RNA; CEF, chicken embryo fibroblast; Epo, erythropoietin; SRE, serum response element; BLK, B lymphocyte kinase; HEK, human embryonic kidney; RCAS, replication-competent avian sarcoma leukosis virus LTR with splice acceptor.


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