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A Novel Function for the Tumor Suppressor p16(INK4a) : Induction of Anoikis via Upregulation of the α(5)β(1) Fibronectin Receptor
The tumor suppressor gene p16(INK4a) inhibits the kinase activity of the cyclin-dependent kinase 4–6/cyclin D complexes and subsequent phosphorylation of critical substrates necessary for transit through the G1 phase of the cell cycle. Recent studies suggested that control of the G1/S boundary might...
Autores principales: | , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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The Rockefeller University Press
2000
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2150704/ https://www.ncbi.nlm.nih.gov/pubmed/10995450 |
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author | Plath, Thomas Detjen, Katharina Welzel, Martina von Marschall, Zofia Murphy, Derek Schirner, Michael Wiedenmann, Bertram Rosewicz, Stefan |
author_facet | Plath, Thomas Detjen, Katharina Welzel, Martina von Marschall, Zofia Murphy, Derek Schirner, Michael Wiedenmann, Bertram Rosewicz, Stefan |
author_sort | Plath, Thomas |
collection | PubMed |
description | The tumor suppressor gene p16(INK4a) inhibits the kinase activity of the cyclin-dependent kinase 4–6/cyclin D complexes and subsequent phosphorylation of critical substrates necessary for transit through the G1 phase of the cell cycle. Recent studies suggested that control of the G1/S boundary might not be the sole biological function of p16(INK4a). We hypothesized that p16(INK4a) might influence hitherto unknown critical features of a malignant epithelial phenotype, such as anchorage dependence. Here we provide evidence that stable transfection of p16(INK4a) restitutes apoptosis induction upon loss of anchorage (anoikis) in a variety of human cancer cells. Anoikis in p16(INK4a)-transfected cells was evidenced by DNA fragmentation and poly(ADP-ribose) polymerase cleavage upon cultivation on polyhydroxyethylmethacrylate-coated dishes and was associated with suppression of anchorage-independent growth as well as complete loss of tumorigenicity. p16(INK4a)-mediated anoikis was due to selective transcriptional upregulation of the α(5) integrin chain of the α(5)β(1) fibronectin receptor as detected by FACS(®) analysis, immunoprecipitation, Northern blotting, and nuclear run-on assays. Addition of soluble fibronectin and inhibitory α(5) antibodies to nonadherent cells completely abolished p16(INK4a)-mediated anoikis, whereas laminin was ineffective. Furthermore, antisense-induced downregulation of the α(5) integrin chain in p16(INK4a)-transfected cells restored resistance to anoikis. These data suggest a novel functional interference between a cell cycle–regulating tumor suppressor gene and membrane-bound integrins, thus regulating a hallmark feature of an epithelial transformed phenotype: susceptibility to anoikis. |
format | Text |
id | pubmed-2150704 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2000 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-21507042008-05-01 A Novel Function for the Tumor Suppressor p16(INK4a) : Induction of Anoikis via Upregulation of the α(5)β(1) Fibronectin Receptor Plath, Thomas Detjen, Katharina Welzel, Martina von Marschall, Zofia Murphy, Derek Schirner, Michael Wiedenmann, Bertram Rosewicz, Stefan J Cell Biol Original Article The tumor suppressor gene p16(INK4a) inhibits the kinase activity of the cyclin-dependent kinase 4–6/cyclin D complexes and subsequent phosphorylation of critical substrates necessary for transit through the G1 phase of the cell cycle. Recent studies suggested that control of the G1/S boundary might not be the sole biological function of p16(INK4a). We hypothesized that p16(INK4a) might influence hitherto unknown critical features of a malignant epithelial phenotype, such as anchorage dependence. Here we provide evidence that stable transfection of p16(INK4a) restitutes apoptosis induction upon loss of anchorage (anoikis) in a variety of human cancer cells. Anoikis in p16(INK4a)-transfected cells was evidenced by DNA fragmentation and poly(ADP-ribose) polymerase cleavage upon cultivation on polyhydroxyethylmethacrylate-coated dishes and was associated with suppression of anchorage-independent growth as well as complete loss of tumorigenicity. p16(INK4a)-mediated anoikis was due to selective transcriptional upregulation of the α(5) integrin chain of the α(5)β(1) fibronectin receptor as detected by FACS(®) analysis, immunoprecipitation, Northern blotting, and nuclear run-on assays. Addition of soluble fibronectin and inhibitory α(5) antibodies to nonadherent cells completely abolished p16(INK4a)-mediated anoikis, whereas laminin was ineffective. Furthermore, antisense-induced downregulation of the α(5) integrin chain in p16(INK4a)-transfected cells restored resistance to anoikis. These data suggest a novel functional interference between a cell cycle–regulating tumor suppressor gene and membrane-bound integrins, thus regulating a hallmark feature of an epithelial transformed phenotype: susceptibility to anoikis. The Rockefeller University Press 2000-09-18 /pmc/articles/PMC2150704/ /pubmed/10995450 Text en © 2000 The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Original Article Plath, Thomas Detjen, Katharina Welzel, Martina von Marschall, Zofia Murphy, Derek Schirner, Michael Wiedenmann, Bertram Rosewicz, Stefan A Novel Function for the Tumor Suppressor p16(INK4a) : Induction of Anoikis via Upregulation of the α(5)β(1) Fibronectin Receptor |
title | A Novel Function for the Tumor Suppressor p16(INK4a)
: Induction of Anoikis via Upregulation of the α(5)β(1) Fibronectin Receptor |
title_full | A Novel Function for the Tumor Suppressor p16(INK4a)
: Induction of Anoikis via Upregulation of the α(5)β(1) Fibronectin Receptor |
title_fullStr | A Novel Function for the Tumor Suppressor p16(INK4a)
: Induction of Anoikis via Upregulation of the α(5)β(1) Fibronectin Receptor |
title_full_unstemmed | A Novel Function for the Tumor Suppressor p16(INK4a)
: Induction of Anoikis via Upregulation of the α(5)β(1) Fibronectin Receptor |
title_short | A Novel Function for the Tumor Suppressor p16(INK4a)
: Induction of Anoikis via Upregulation of the α(5)β(1) Fibronectin Receptor |
title_sort | novel function for the tumor suppressor p16(ink4a)
: induction of anoikis via upregulation of the α(5)β(1) fibronectin receptor |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2150704/ https://www.ncbi.nlm.nih.gov/pubmed/10995450 |
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