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Oncogene (2004) 23, 53945404
& 2004 Nature Publishing Group All rights reserved 0950-9232/04 $30.00www.nature.com/oncA novel crosstalk mechanism between nuclear receptor-mediated and
growth factor/Ras-mediated pathways through PNRCGrb2interactionDujin Zhou1, Bin Chen2, Jing-Jing Ye1 and Shiuan Chen*,11Department of Surgical Research, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA;2Department of Biochemistry, The Third Military Medical University, Chongqing, Peoples Republic of ChinaIt has been demonstrated that proline-rich nuclear
receptor coregulatory protein (PNRC) is a nuclear
receptor coactivator that interacts with nuclear receptors
through an SH3-binding motif located in its C-terminus.
In the present report, a physical interaction between
PNRC and Grb2(an adapter protein involved in growth
factor/Ras-mediated pathways) has been demonstrated
using the GST pull-down assay, the yeast two-hybrid
assay, as well as by coimmunoprecipitation. Cotransfection and uorescence imaging have also conrmed the
colocalization of PNRC and Grb2in mammalian cells.
Transient transfection experiments have demonstrated
that, by interacting with each other, Grb2decreases the
coactivator activity of PNRC for nuclear receptors, and
that PNRC suppresses Grb2-mediated Ras/MAP-kinase
activation. Furthermore, it was discovered that HeLa cells
overexpressing PNRC grew more slowly when compared
to matched controls. Additionally, using a RTPCR
analysis of mRNA on six pairs of cancer/noncancer
tissues, PNRC expression was found to be signicantly
lower in breast cancer tissue than in noncancer tissue.
Based on these ndings, we believe that PNRC and Grb2,
by interacting with each other, can suppress nuclear
receptor-mediated regulation and growth factor-mediated
regulation in human breast tissue. This is a newly
identied crosstalk mechanism for modulating these two
important types of regulatory pathways.Oncogene (2004) 23, 53945404. doi:10.1038/sj.onc.1207695
Published online 3 May 2004Keywords: PNRC; nuclear receptor coactivator; Grb2;
growth factor/Ras; signal transductionIntroductionNuclear receptor-mediated signaling is an important
regulatory pathway in cells. Ligand-bound nuclear
receptors are transcriptional factors that modulate
transcription of various cellular genes, either positively
or negatively, by interacting with specic hormoneresponsive elements located in the target gene promoters, thereby controlling diverse aspects of cell
growth, development, and homeostasis. Recent scientic
studies have reported that in addition to contacting the
basal transcriptional machinery directly, nuclear receptors enhance or inhibit transcription by recruiting an
array of coactivator (Horwitz et al., 1996; Glass et al.,
1997) and corepressor (Ordentlich et al., 2001) proteins
to the transcription complex. Most of the cofactors of
nuclear receptors...