p27kip1 Regulates cdk2 Activity in the Proliferating Zone of the Mouse Intestinal Epithelium: Potential Role in Neoplasia

Helena J M Smartt, Sandra Guilmeau, Shannon V. Nasser, Courtney Nicholas, Laura Bancroft, Sharon A. Simpson, Nancy Yeh, Wancai Yang, John M. Mariadason, Andrew Koff, Leonard H. Augenlicht

Research output: Contribution to journalArticle

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Abstract

Background & Aims: Reduced p27kip1 expression is a marker of poor prognosis in colorectal neoplasia, and inactivation of p27 in mice (p27Δ51/Δ51) causes increased intestinal epithelial cell proliferation and small and large intestinal neoplasia in a diet-dependent manner. Here, we addressed the role of p27 in untransformed intestinal epithelial cells in vivo and the consequence of its targeted inactivation. Methods: A sequential fractionation procedure was used to isolate murine intestinal epithelial cells relative to their position along the crypt-villus axis, and the levels of cyclins, cyclin-dependent kinases (cdks), and cdk inhibitors and of the complexes formed among them was determined by immunoprecipitation-immunoblotting and kinase assays. Results: As cells exited the proliferative crypt compartment, expression and activity of both cdk2 and cdk4 decreased, in parallel with reduced expression of cyclin A and proliferating cell nuclear antigen (PCNA); expression of cyclin D1, D2, and cyclin E showed little change. As expected, expression of the cdk inhibitors p21, p57, and p16 was highest in differentiated villus cells. Unexpectedly, p27 protein expression was highest in cells of the proliferative crypt compartment where it bound both cdk2 and cdk4. Cdk2 activity was increased in crypt cells from p27Δ51/Δ51 mice, although cyclin D-associated kinase activity was unchanged (indeed, cyclin D1/2-cdk4 complex levels were reduced). Importantly, cdk2 activity was unchanged in crypt cells from p21-/- mice, which do not develop intestinal tumors. Conclusions: We propose that p27 contributes to intestinal epithelial homeostasis by regulating cdk2 activity in proliferating cells, thus gating cell cycle progression and suppressing intestinal neoplasia.

Original languageEnglish (US)
Pages (from-to)232-243
Number of pages12
JournalGastroenterology
Volume133
Issue number1
DOIs
StatePublished - Jun 2007

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Intestinal Mucosa
Neoplasms
Epithelial Cells
Cyclin D1
Phosphotransferases
Cyclin D2
Cyclin D
Cyclin A
Cyclin E
Cyclins
Cyclin-Dependent Kinases
Proliferating Cell Nuclear Antigen
Immunoprecipitation
Immunoblotting
Cell Cycle
Homeostasis
Cell Proliferation
Diet
Proteins

ASJC Scopus subject areas

  • Gastroenterology

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p27kip1 Regulates cdk2 Activity in the Proliferating Zone of the Mouse Intestinal Epithelium : Potential Role in Neoplasia. / Smartt, Helena J M; Guilmeau, Sandra; Nasser, Shannon V.; Nicholas, Courtney; Bancroft, Laura; Simpson, Sharon A.; Yeh, Nancy; Yang, Wancai; Mariadason, John M.; Koff, Andrew; Augenlicht, Leonard H.

In: Gastroenterology, Vol. 133, No. 1, 06.2007, p. 232-243.

Research output: Contribution to journalArticle

Smartt, HJM, Guilmeau, S, Nasser, SV, Nicholas, C, Bancroft, L, Simpson, SA, Yeh, N, Yang, W, Mariadason, JM, Koff, A & Augenlicht, LH 2007, 'p27kip1 Regulates cdk2 Activity in the Proliferating Zone of the Mouse Intestinal Epithelium: Potential Role in Neoplasia', Gastroenterology, vol. 133, no. 1, pp. 232-243. https://doi.org/10.1053/j.gastro.2007.04.043
Smartt, Helena J M ; Guilmeau, Sandra ; Nasser, Shannon V. ; Nicholas, Courtney ; Bancroft, Laura ; Simpson, Sharon A. ; Yeh, Nancy ; Yang, Wancai ; Mariadason, John M. ; Koff, Andrew ; Augenlicht, Leonard H. / p27kip1 Regulates cdk2 Activity in the Proliferating Zone of the Mouse Intestinal Epithelium : Potential Role in Neoplasia. In: Gastroenterology. 2007 ; Vol. 133, No. 1. pp. 232-243.
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abstract = "Background & Aims: Reduced p27kip1 expression is a marker of poor prognosis in colorectal neoplasia, and inactivation of p27 in mice (p27Δ51/Δ51) causes increased intestinal epithelial cell proliferation and small and large intestinal neoplasia in a diet-dependent manner. Here, we addressed the role of p27 in untransformed intestinal epithelial cells in vivo and the consequence of its targeted inactivation. Methods: A sequential fractionation procedure was used to isolate murine intestinal epithelial cells relative to their position along the crypt-villus axis, and the levels of cyclins, cyclin-dependent kinases (cdks), and cdk inhibitors and of the complexes formed among them was determined by immunoprecipitation-immunoblotting and kinase assays. Results: As cells exited the proliferative crypt compartment, expression and activity of both cdk2 and cdk4 decreased, in parallel with reduced expression of cyclin A and proliferating cell nuclear antigen (PCNA); expression of cyclin D1, D2, and cyclin E showed little change. As expected, expression of the cdk inhibitors p21, p57, and p16 was highest in differentiated villus cells. Unexpectedly, p27 protein expression was highest in cells of the proliferative crypt compartment where it bound both cdk2 and cdk4. Cdk2 activity was increased in crypt cells from p27Δ51/Δ51 mice, although cyclin D-associated kinase activity was unchanged (indeed, cyclin D1/2-cdk4 complex levels were reduced). Importantly, cdk2 activity was unchanged in crypt cells from p21-/- mice, which do not develop intestinal tumors. Conclusions: We propose that p27 contributes to intestinal epithelial homeostasis by regulating cdk2 activity in proliferating cells, thus gating cell cycle progression and suppressing intestinal neoplasia.",
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T1 - p27kip1 Regulates cdk2 Activity in the Proliferating Zone of the Mouse Intestinal Epithelium

T2 - Potential Role in Neoplasia

AU - Smartt, Helena J M

AU - Guilmeau, Sandra

AU - Nasser, Shannon V.

AU - Nicholas, Courtney

AU - Bancroft, Laura

AU - Simpson, Sharon A.

AU - Yeh, Nancy

AU - Yang, Wancai

AU - Mariadason, John M.

AU - Koff, Andrew

AU - Augenlicht, Leonard H.

PY - 2007/6

Y1 - 2007/6

N2 - Background & Aims: Reduced p27kip1 expression is a marker of poor prognosis in colorectal neoplasia, and inactivation of p27 in mice (p27Δ51/Δ51) causes increased intestinal epithelial cell proliferation and small and large intestinal neoplasia in a diet-dependent manner. Here, we addressed the role of p27 in untransformed intestinal epithelial cells in vivo and the consequence of its targeted inactivation. Methods: A sequential fractionation procedure was used to isolate murine intestinal epithelial cells relative to their position along the crypt-villus axis, and the levels of cyclins, cyclin-dependent kinases (cdks), and cdk inhibitors and of the complexes formed among them was determined by immunoprecipitation-immunoblotting and kinase assays. Results: As cells exited the proliferative crypt compartment, expression and activity of both cdk2 and cdk4 decreased, in parallel with reduced expression of cyclin A and proliferating cell nuclear antigen (PCNA); expression of cyclin D1, D2, and cyclin E showed little change. As expected, expression of the cdk inhibitors p21, p57, and p16 was highest in differentiated villus cells. Unexpectedly, p27 protein expression was highest in cells of the proliferative crypt compartment where it bound both cdk2 and cdk4. Cdk2 activity was increased in crypt cells from p27Δ51/Δ51 mice, although cyclin D-associated kinase activity was unchanged (indeed, cyclin D1/2-cdk4 complex levels were reduced). Importantly, cdk2 activity was unchanged in crypt cells from p21-/- mice, which do not develop intestinal tumors. Conclusions: We propose that p27 contributes to intestinal epithelial homeostasis by regulating cdk2 activity in proliferating cells, thus gating cell cycle progression and suppressing intestinal neoplasia.

AB - Background & Aims: Reduced p27kip1 expression is a marker of poor prognosis in colorectal neoplasia, and inactivation of p27 in mice (p27Δ51/Δ51) causes increased intestinal epithelial cell proliferation and small and large intestinal neoplasia in a diet-dependent manner. Here, we addressed the role of p27 in untransformed intestinal epithelial cells in vivo and the consequence of its targeted inactivation. Methods: A sequential fractionation procedure was used to isolate murine intestinal epithelial cells relative to their position along the crypt-villus axis, and the levels of cyclins, cyclin-dependent kinases (cdks), and cdk inhibitors and of the complexes formed among them was determined by immunoprecipitation-immunoblotting and kinase assays. Results: As cells exited the proliferative crypt compartment, expression and activity of both cdk2 and cdk4 decreased, in parallel with reduced expression of cyclin A and proliferating cell nuclear antigen (PCNA); expression of cyclin D1, D2, and cyclin E showed little change. As expected, expression of the cdk inhibitors p21, p57, and p16 was highest in differentiated villus cells. Unexpectedly, p27 protein expression was highest in cells of the proliferative crypt compartment where it bound both cdk2 and cdk4. Cdk2 activity was increased in crypt cells from p27Δ51/Δ51 mice, although cyclin D-associated kinase activity was unchanged (indeed, cyclin D1/2-cdk4 complex levels were reduced). Importantly, cdk2 activity was unchanged in crypt cells from p21-/- mice, which do not develop intestinal tumors. Conclusions: We propose that p27 contributes to intestinal epithelial homeostasis by regulating cdk2 activity in proliferating cells, thus gating cell cycle progression and suppressing intestinal neoplasia.

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