Notch signaling is required for normal prostatic epithelial cell proliferation and differentiation.
Notch pathway is crucial for stem/progenitor cell maintenance, growth and differentiation in a variety of tissues. Using a transgenic cell ablation approach, we found in our previous study that cells expressing Notch1 are crucial for prostate early development and re-growth. Here, we further define the role of Notch signaling in regulating prostatic epithelial cell growth and differentiation using biochemical and genetic approaches in ex vivo or in vivo systems. Treatment of developing prostate grown in culture with inhibitors of gamma-secretase/presenilin, which is required for Notch cleavage and activation, caused a robust increase in proliferation of epithelial cells co-expressing cytokeratin 8 and 14, lack of luminal/basal layer segregation and dramatically reduced branching morphogenesis. Using conditional Notch1 gene deletion mouse models, we found that inactivation of Notch1 signaling resulted in profound prostatic alterations, including increased tufting, bridging and enhanced epithelial proliferation. Cells within these lesions co-expressed both luminal and basal cell markers, a feature of prostatic epithelial cells in predifferentiation developmental stages. Microarray analysis revealed that the gene expression in a number of genetic networks was altered following Notch1 gene deletion in prostate. Furthermore, expression of Notch1 and its effector Hey-1 gene in human prostate adenocarcinomas were found significantly down-regulated compared to normal control tissues. Taken together, these data suggest that Notch signaling is critical for normal cell proliferation and differentiation in the prostate, and deregulation of this pathway may facilitate prostatic tumorigenesis.
Wang
Xi-De
XD
Department of Molecular Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Leow
Ching Ching
CC
Zha
Jiping
J
Tang
Zhijun
Z
Modrusan
Zora
Z
Radtke
Freddy
F
Aguet
Michel
M
de Sauvage
Frederic J
FJ
Gao
Wei-Qiang
WQ
D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D000831:Animals, Newborn; D016282:Aspartic Acid Endopeptidases; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D015536:Down-Regulation; D010450:Endopeptidases / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007633:Keratins / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis; D020411:Oligonucleotide Array Sequence Analysis; D011467:Prostate / Q000254:growth & development / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*
D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D010450:Endopeptidases; D007633:Keratins; D011480:Protease Inhibitors; D051881:Receptor, Notch1; C485631:HEY1 protein, human; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse