Induction of the tumor-suppressor p16(INK4a) within regenerative epithelial crypts in ulcerative colitis.
p16(INK4a) is a major tumor-suppressor protein, but its regulation and settings of fuction remain poorly understood. To explore the notion that p16 is induced in vivo in response to replicative stress, we examined p16 expression in tissues from human ulcerative colitis (UC; n = 25) and normal controls (n = 20). p16 was expressed strongly in UC-associated neoplasms (n = 17), as seen previously in sporadic colonic neoplasms. In non-neoplastic UC epithelium, p16 was expressed in 33% of crypts (the proliferative compartment) compared to < 1% of normal controls. p16 expression did not correlate with degree of inflammation but did correlate with the degree of crypt architecture distortion (P = .002)-a reflection of epithelial regeneration. In coimmunofluorescence studies with Ki67, p16 expression was associated with cell cycle arrest (P < .001). Both UC and normal crypts displayed evidence for the activation of the DNA damage checkpoint pathway, and p16 was induced in primary cultures of normal epithelial cells by ionizing irradiation (IR). However, induction by IR displayed delayed kinetics, implying that p16 is not an immediate target of the checkpoint pathway. These findings support a model in which p16 is induced as an "emergency brake" in cells experiencing sustained replicative stress.
Furth
Emma E
EE
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Gustafson
Karen S
KS
Dai
Charlotte Y
CY
Gibson
Steven L
SL
Menard-Katcher
Paul
P
Chen
Tina
T
Koh
Jim
J
Enders
Greg H
GH
D003093:Colitis, Ulcerative / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis*; D004249:DNA Damage; D004847:Epithelial Cells / Q000166:cytology; D004848:Epithelium / Q000473:pathology; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007249:Inflammation; D007413:Intestinal Mucosa / Q000473:pathology; D019394:Ki-67 Antigen / Q000096:biosynthesis; D007700:Kinetics; D008856:Microscopy, Fluorescence; D012038:Regeneration
D019941:Cyclin-Dependent Kinase Inhibitor p16; D019394:Ki-67 Antigen