A prostatic intraepithelial neoplasia-dependent p27 Kip1 checkpoint induces senescence and inhibits cell proliferation and cancer progression.
Transgenic expression of activated AKT1 in the murine prostate induces prostatic intraepithelial neoplasia (PIN) that does not progress to invasive prostate cancer (CaP). In luminal epithelial cells of Akt-driven PIN, we show the concomitant induction of p27(Kip1) and senescence. Genetic ablation of p27(Kip1) led to downregulation of senescence markers and progression to cancer. In humans, p27(Kip1) and senescence markers were elevated in PIN not associated with CaP but were decreased or absent, respectively, in cancer-associated PIN and in CaP. Importantly, p27(Kip1) upregulation in mouse and human in situ lesions did not depend upon mTOR or Akt activation but was instead specifically associated with alterations in cell polarity, architecture, and adhesion molecules. These data suggest that a p27(Kip1)-driven checkpoint limits progression of PIN to CaP.
Majumder
Pradip K
PK
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Grisanzio
Chiara
C
O'Connell
Fionnuala
F
Barry
Marc
M
Brito
Joseph M
JM
Xu
Qing
Q
Guney
Isil
I
Berger
Raanan
R
Herman
Paula
P
Bikoff
Rachel
R
Fedele
Giuseppe
G
Baek
Won-Ki
WK
Wang
Shunyou
S
Ellwood-Yen
Katharine
K
Wu
Hong
H
Sawyers
Charles L
CL
Signoretti
Sabina
S
Hahn
William C
WC
Loda
Massimo
M
Sellers
William R
WR
D000483:Alleles; D000818:Animals; D030801:Animals, Genetically Modified; D015415:Biomarkers / Q000378:metabolism; D002448:Cell Adhesion; D002450:Cell Communication; D002460:Cell Line; D016764:Cell Polarity; D049109:Cell Proliferation; D016922:Cellular Senescence; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D018450:Disease Progression; D004847:Epithelial Cells / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D019048:Prostatic Intraepithelial Neoplasia / Q000378:metabolism* / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D058570:TOR Serine-Threonine Kinases
D015415:Biomarkers; D050760:Cyclin-Dependent Kinase Inhibitor p27; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases