Pten deficiency activates distinct downstream signaling pathways in a tissue-specific manner.
PTEN deficiency predisposes to a subset of human cancers, but the mechanism that underlies such selectivity is unknown. We have generated a mouse line that conditionally deletes Pten in urogenital epithelium. These mice develop carcinomas at high frequency in the prostate but at relatively low frequency in the bladder, despite early and complete penetrance of hyperplasia in both organs. Cell proliferation is initially high in the bladder of newborn Pten-deficient mice but within days is inhibited by p21 induction. In contrast, proliferation remains elevated in Pten-deficient prostate, where p21 is never induced, suggesting that p21 induction is a bladder-specific compensatory mechanism to inhibit proliferation caused by Pten deletion. Furthermore, the AKT/mammalian target of rapamycin growth pathway, which is highly activated in Pten-deficient prostate, is not activated in bladder epithelium. Our results reveal alternative downstream signaling pathways activated by Pten deficiency that lead to tissue-specific susceptibilities to tumorigenesis.
Yoo
Lina I
LI
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Liu
David W
DW
Le Vu
Sandrine
S
Bronson
Roderick T
RT
Wu
Hong
H
Yuan
Junying
J
D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D005260:Female; D006965:Hyperplasia; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics; D011467:Prostate / Q000201:enzymology / Q000473:pathology; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D001743:Urinary Bladder / Q000201:enzymology / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000201:enzymology / Q000473:pathology; D014565:Urogenital Neoplasms / Q000201:enzymology* / Q000473:pathology; D019459:Urothelium / Q000201:enzymology / Q000473:pathology; D014621:Vagina / Q000201:enzymology / Q000473:pathology
D050759:Cyclin-Dependent Kinase Inhibitor p21; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse