Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon
Michael Overholtzer1, Jianmin Zhang, Gromoslaw A Smolen
1Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Abstract:
In a screen for gene copy-number changes in mouse mammary tumors, we identified a tumor with a small 350-kb amplicon from a region that is syntenic to a much larger locus amplified in human cancers at chromosome 11q22. The mouse amplicon contains only one known gene, Yap, encoding the mammalian ortholog of Drosophila Yorkie (Yki), a downstream effector of the Hippo(Hpo)-Salvador(Sav)-Warts(Wts) signaling cascade, recently identified in flies as a critical regulator of cellular proliferation and apoptosis. In nontransformed mammary epithelial cells, overexpression of human YAP induces epithelial-to-mesenchymal transition, suppression of apoptosis, growth factor-independent proliferation, and anchorage-independent growth in soft agar. Together, these observations point to a potential oncogenic role for YAP in 11q22-amplified human cancers, and they suggest that this highly conserved signaling pathway identified in Drosophila regulates both cellular proliferation and apoptosis in mammalian epithelial cells.
Insights
Researchers found that YAP, a gene linked to cancer, is amplified in mouse mammary tumors. Overexpression of YAP in human cells promoted cancer-like growth, suggesting its oncogenic role in human cancers.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- Gene copy-number alterations are implicated in tumorigenesis.
- The Hippo-Salvador-Warts signaling pathway regulates proliferation and apoptosis in Drosophila.
- The mammalian ortholog of Drosophila Yorkie (Yki) is Yap.
Purpose of the Study:
- To investigate the role of gene copy-number changes in mouse mammary tumors.
- To identify potential oncogenes in amplified regions syntenic to human cancer loci.
- To explore the function of Yap in mammalian epithelial cells.
Main Methods:
- Comparative genomic hybridization (CGH) or similar techniques to screen for gene copy-number changes in mouse mammary tumors.
- Identification and characterization of amplified genes within mouse amplicons.
- Overexpression studies of human YAP in nontransformed mammary epithelial cells.
- Assessment of cellular phenotypes including epithelial-to-mesenchymal transition, apoptosis, proliferation, and anchorage-independent growth.
Main Results:
- A 350-kb amplicon was identified in a mouse mammary tumor, syntenic to human chromosome 11q22.
- The mouse amplicon contains the Yap gene, the mammalian ortholog of Drosophila Yki.
- Overexpression of human YAP in mammary epithelial cells induced epithelial-to-mesenchymal transition, suppressed apoptosis, and promoted growth factor-independent and anchorage-independent proliferation.
Conclusions:
- The Yap gene plays a potential oncogenic role in human cancers with 11q22 amplification.
- The conserved Hippo-Salvador-Warts signaling pathway regulates cellular proliferation and apoptosis in mammalian epithelial cells.
- YAP is a potential therapeutic target in relevant human cancers.
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