Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon.
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.
Overholtzer
Michael
M
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Zhang
Jianmin
J
Smolen
Gromoslaw A
GA
Muir
Beth
B
Li
Wenmei
W
Sgroi
Dennis C
DC
Deng
Chu-Xia
CX
Brugge
Joan S
JS
Haber
Daniel A
DA
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D048430:Cell Shape; D002471:Cell Transformation, Neoplastic; D002880:Chromosomes, Human, Pair 11; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009857:Oncogenes; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D015534:Trans-Activators; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; C503814:Yki protein, Drosophila