Induction of the Tumor-Suppressor p16INK4a within Regenerative Epithelial Crypts in Ulcerative Colitis
p16INK4a 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...
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Format: | Article |
Language: | English |
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Elsevier
2006-06-01
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Series: | Neoplasia: An International Journal for Oncology Research |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558606800254 |
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author | Emma E. Furth Karen S. Gustafson Charlotte Y. Dai Steven L. Gibson Paul Menard-Katcher Tina Chen Jim Koh Greg H. Enders |
author_facet | Emma E. Furth Karen S. Gustafson Charlotte Y. Dai Steven L. Gibson Paul Menard-Katcher Tina Chen Jim Koh Greg H. Enders |
author_sort | Emma E. Furth |
collection | DOAJ |
description | p16INK4a 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. |
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id | doaj.art-d9f9ddbb80d84af1adfff90997b74486 |
institution | Directory Open Access Journal |
issn | 1476-5586 1522-8002 |
language | English |
last_indexed | 2024-04-13T05:18:52Z |
publishDate | 2006-06-01 |
publisher | Elsevier |
record_format | Article |
series | Neoplasia: An International Journal for Oncology Research |
spelling | doaj.art-d9f9ddbb80d84af1adfff90997b744862022-12-22T03:00:49ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022006-06-018642943610.1593/neo.06169Induction of the Tumor-Suppressor p16INK4a within Regenerative Epithelial Crypts in Ulcerative ColitisEmma E. Furth0Karen S. Gustafson1Charlotte Y. Dai2Steven L. Gibson3Paul Menard-Katcher4Tina Chen5Jim Koh6Greg H. Enders7Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USADepartment of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USADepartment of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USADepartment of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USADepartment of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USADepartment of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USADivision of Neurosurgery, Department of Surgery, Duke University Medical School, Durham, NC, USADepartment of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USAp16INK4a 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.http://www.sciencedirect.com/science/article/pii/S1476558606800254p16INK4aulcerative colitistumor suppressorDNA damage |
spellingShingle | Emma E. Furth Karen S. Gustafson Charlotte Y. Dai Steven L. Gibson Paul Menard-Katcher Tina Chen Jim Koh Greg H. Enders Induction of the Tumor-Suppressor p16INK4a within Regenerative Epithelial Crypts in Ulcerative Colitis Neoplasia: An International Journal for Oncology Research p16 INK4a ulcerative colitis tumor suppressor DNA damage |
title | Induction of the Tumor-Suppressor p16INK4a within Regenerative Epithelial Crypts in Ulcerative Colitis |
title_full | Induction of the Tumor-Suppressor p16INK4a within Regenerative Epithelial Crypts in Ulcerative Colitis |
title_fullStr | Induction of the Tumor-Suppressor p16INK4a within Regenerative Epithelial Crypts in Ulcerative Colitis |
title_full_unstemmed | Induction of the Tumor-Suppressor p16INK4a within Regenerative Epithelial Crypts in Ulcerative Colitis |
title_short | Induction of the Tumor-Suppressor p16INK4a within Regenerative Epithelial Crypts in Ulcerative Colitis |
title_sort | induction of the tumor suppressor p16ink4a within regenerative epithelial crypts in ulcerative colitis |
topic | p16 INK4a ulcerative colitis tumor suppressor DNA damage |
url | http://www.sciencedirect.com/science/article/pii/S1476558606800254 |
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