Loss of caveolin-1 causes the hyper-proliferation of intestinal crypt stem cells, with increased sensitivity to whole body γ-radiation

Jiangwei Li, Ghada S. Hassan, Terence M. Williams, Carlo Minetti, Richard G. Pestell, Herbert B. Tanowitz, Philippe G. Frank, Federica Sotgia, Michael P. Lisanti

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

Caveolin-1 (Cav-1) is a protein marker for caveolae organelles, and acts as a scaffolding protein to negatively regulate the activity of signaling molecules by binding to and releasing them in a timely fashion. We have previously shown that loss of Cav-1 promotes the proliferation of mouse embryo fibroblasts (MEFs) in vitro. Here, to investigate the in vivo relevance of these findings, we evaluated the turnover rates of small intestine crypt stem cells from WT and Cav-1 deficient mice. Interestingly, we show that Cav-1 null crypt stem cells display higher proliferation rates, as judged by BrdU and PCNA staining. In addition, we show that Wnt/β-catenin signaling, which normally controls intestinal stem cell self-renewal, is up-regulated in Cav-1 deficient crypt stem cells. Because the small intestine constitutes one of the main targets of radiation, we next evaluated the role of Cav-1 in radiation-induced damage. Interestingly, after exposure to 15 Gy of γ-radiation, Cav-1 deficient mice displayed a decreased survival rate, as compared to WT mice. Our results show that after radiation treatment, Cav-1 null crypt stem cells of the small intestine exhibit far more apoptosis and accelerated proliferation, leading to a faster depletion of crypts and villi. As a consequence, six days after radiation treatment, Cav-1-/- mice lost all their crypt and villus structures, while WT mice still showed some crypts and intact villi. In summary, we show that ablation of Cav-1 gene expression induces an abnormal amplification of crypt stem cells, resulting in increased susceptibility to γ-radiation. Thus, our studies provide the first evidence that Cav-1 normally regulates the proliferation of intestinal stem cells in vivo.

Original languageEnglish (US)
Pages (from-to)1817-1825
Number of pages9
JournalCell Cycle
Volume4
Issue number12
StatePublished - Dec 2005

Fingerprint

Caveolin 1
Whole-Body Irradiation
Stem cells
Stem Cells
Radiation
Small Intestine
Radiation Dosage
Caveolae
Catenins
Proliferating Cell Nuclear Antigen
Bromodeoxyuridine
Fibroblasts
Ablation
Gene expression
Organelles
Amplification
Proteins
Embryonic Structures

Keywords

  • β-catenin
  • Apoptosis
  • Caveolae
  • Caveolin-1
  • Crypt stem cells
  • Intestinal progenitor cells
  • Proliferation
  • Radiation treatment

ASJC Scopus subject areas

  • Cell Biology
  • Biochemistry
  • Molecular Biology

Cite this

Li, J., Hassan, G. S., Williams, T. M., Minetti, C., Pestell, R. G., Tanowitz, H. B., ... Lisanti, M. P. (2005). Loss of caveolin-1 causes the hyper-proliferation of intestinal crypt stem cells, with increased sensitivity to whole body γ-radiation. Cell Cycle, 4(12), 1817-1825.

Loss of caveolin-1 causes the hyper-proliferation of intestinal crypt stem cells, with increased sensitivity to whole body γ-radiation. / Li, Jiangwei; Hassan, Ghada S.; Williams, Terence M.; Minetti, Carlo; Pestell, Richard G.; Tanowitz, Herbert B.; Frank, Philippe G.; Sotgia, Federica; Lisanti, Michael P.

In: Cell Cycle, Vol. 4, No. 12, 12.2005, p. 1817-1825.

Research output: Contribution to journalArticle

Li, J, Hassan, GS, Williams, TM, Minetti, C, Pestell, RG, Tanowitz, HB, Frank, PG, Sotgia, F & Lisanti, MP 2005, 'Loss of caveolin-1 causes the hyper-proliferation of intestinal crypt stem cells, with increased sensitivity to whole body γ-radiation', Cell Cycle, vol. 4, no. 12, pp. 1817-1825.
Li J, Hassan GS, Williams TM, Minetti C, Pestell RG, Tanowitz HB et al. Loss of caveolin-1 causes the hyper-proliferation of intestinal crypt stem cells, with increased sensitivity to whole body γ-radiation. Cell Cycle. 2005 Dec;4(12):1817-1825.
Li, Jiangwei ; Hassan, Ghada S. ; Williams, Terence M. ; Minetti, Carlo ; Pestell, Richard G. ; Tanowitz, Herbert B. ; Frank, Philippe G. ; Sotgia, Federica ; Lisanti, Michael P. / Loss of caveolin-1 causes the hyper-proliferation of intestinal crypt stem cells, with increased sensitivity to whole body γ-radiation. In: Cell Cycle. 2005 ; Vol. 4, No. 12. pp. 1817-1825.
@article{198d8be50517419bbf4831f4083a0283,
title = "Loss of caveolin-1 causes the hyper-proliferation of intestinal crypt stem cells, with increased sensitivity to whole body γ-radiation",
abstract = "Caveolin-1 (Cav-1) is a protein marker for caveolae organelles, and acts as a scaffolding protein to negatively regulate the activity of signaling molecules by binding to and releasing them in a timely fashion. We have previously shown that loss of Cav-1 promotes the proliferation of mouse embryo fibroblasts (MEFs) in vitro. Here, to investigate the in vivo relevance of these findings, we evaluated the turnover rates of small intestine crypt stem cells from WT and Cav-1 deficient mice. Interestingly, we show that Cav-1 null crypt stem cells display higher proliferation rates, as judged by BrdU and PCNA staining. In addition, we show that Wnt/β-catenin signaling, which normally controls intestinal stem cell self-renewal, is up-regulated in Cav-1 deficient crypt stem cells. Because the small intestine constitutes one of the main targets of radiation, we next evaluated the role of Cav-1 in radiation-induced damage. Interestingly, after exposure to 15 Gy of γ-radiation, Cav-1 deficient mice displayed a decreased survival rate, as compared to WT mice. Our results show that after radiation treatment, Cav-1 null crypt stem cells of the small intestine exhibit far more apoptosis and accelerated proliferation, leading to a faster depletion of crypts and villi. As a consequence, six days after radiation treatment, Cav-1-/- mice lost all their crypt and villus structures, while WT mice still showed some crypts and intact villi. In summary, we show that ablation of Cav-1 gene expression induces an abnormal amplification of crypt stem cells, resulting in increased susceptibility to γ-radiation. Thus, our studies provide the first evidence that Cav-1 normally regulates the proliferation of intestinal stem cells in vivo.",
keywords = "β-catenin, Apoptosis, Caveolae, Caveolin-1, Crypt stem cells, Intestinal progenitor cells, Proliferation, Radiation treatment",
author = "Jiangwei Li and Hassan, {Ghada S.} and Williams, {Terence M.} and Carlo Minetti and Pestell, {Richard G.} and Tanowitz, {Herbert B.} and Frank, {Philippe G.} and Federica Sotgia and Lisanti, {Michael P.}",
year = "2005",
month = "12",
language = "English (US)",
volume = "4",
pages = "1817--1825",
journal = "Cell Cycle",
issn = "1538-4101",
publisher = "Landes Bioscience",
number = "12",

}

TY - JOUR

T1 - Loss of caveolin-1 causes the hyper-proliferation of intestinal crypt stem cells, with increased sensitivity to whole body γ-radiation

AU - Li, Jiangwei

AU - Hassan, Ghada S.

AU - Williams, Terence M.

AU - Minetti, Carlo

AU - Pestell, Richard G.

AU - Tanowitz, Herbert B.

AU - Frank, Philippe G.

AU - Sotgia, Federica

AU - Lisanti, Michael P.

PY - 2005/12

Y1 - 2005/12

N2 - Caveolin-1 (Cav-1) is a protein marker for caveolae organelles, and acts as a scaffolding protein to negatively regulate the activity of signaling molecules by binding to and releasing them in a timely fashion. We have previously shown that loss of Cav-1 promotes the proliferation of mouse embryo fibroblasts (MEFs) in vitro. Here, to investigate the in vivo relevance of these findings, we evaluated the turnover rates of small intestine crypt stem cells from WT and Cav-1 deficient mice. Interestingly, we show that Cav-1 null crypt stem cells display higher proliferation rates, as judged by BrdU and PCNA staining. In addition, we show that Wnt/β-catenin signaling, which normally controls intestinal stem cell self-renewal, is up-regulated in Cav-1 deficient crypt stem cells. Because the small intestine constitutes one of the main targets of radiation, we next evaluated the role of Cav-1 in radiation-induced damage. Interestingly, after exposure to 15 Gy of γ-radiation, Cav-1 deficient mice displayed a decreased survival rate, as compared to WT mice. Our results show that after radiation treatment, Cav-1 null crypt stem cells of the small intestine exhibit far more apoptosis and accelerated proliferation, leading to a faster depletion of crypts and villi. As a consequence, six days after radiation treatment, Cav-1-/- mice lost all their crypt and villus structures, while WT mice still showed some crypts and intact villi. In summary, we show that ablation of Cav-1 gene expression induces an abnormal amplification of crypt stem cells, resulting in increased susceptibility to γ-radiation. Thus, our studies provide the first evidence that Cav-1 normally regulates the proliferation of intestinal stem cells in vivo.

AB - Caveolin-1 (Cav-1) is a protein marker for caveolae organelles, and acts as a scaffolding protein to negatively regulate the activity of signaling molecules by binding to and releasing them in a timely fashion. We have previously shown that loss of Cav-1 promotes the proliferation of mouse embryo fibroblasts (MEFs) in vitro. Here, to investigate the in vivo relevance of these findings, we evaluated the turnover rates of small intestine crypt stem cells from WT and Cav-1 deficient mice. Interestingly, we show that Cav-1 null crypt stem cells display higher proliferation rates, as judged by BrdU and PCNA staining. In addition, we show that Wnt/β-catenin signaling, which normally controls intestinal stem cell self-renewal, is up-regulated in Cav-1 deficient crypt stem cells. Because the small intestine constitutes one of the main targets of radiation, we next evaluated the role of Cav-1 in radiation-induced damage. Interestingly, after exposure to 15 Gy of γ-radiation, Cav-1 deficient mice displayed a decreased survival rate, as compared to WT mice. Our results show that after radiation treatment, Cav-1 null crypt stem cells of the small intestine exhibit far more apoptosis and accelerated proliferation, leading to a faster depletion of crypts and villi. As a consequence, six days after radiation treatment, Cav-1-/- mice lost all their crypt and villus structures, while WT mice still showed some crypts and intact villi. In summary, we show that ablation of Cav-1 gene expression induces an abnormal amplification of crypt stem cells, resulting in increased susceptibility to γ-radiation. Thus, our studies provide the first evidence that Cav-1 normally regulates the proliferation of intestinal stem cells in vivo.

KW - β-catenin

KW - Apoptosis

KW - Caveolae

KW - Caveolin-1

KW - Crypt stem cells

KW - Intestinal progenitor cells

KW - Proliferation

KW - Radiation treatment

UR - http://www.scopus.com/inward/record.url?scp=29244473885&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=29244473885&partnerID=8YFLogxK

M3 - Article

VL - 4

SP - 1817

EP - 1825

JO - Cell Cycle

JF - Cell Cycle

SN - 1538-4101

IS - 12

ER -