A Novel Function for the Tumor Suppressor p16INK4a: Induction of Anoikis via Upregulation of the α5β1 Fibronectin Receptor (original) (raw)
Article| September 18 2000
aMedizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité, Campus Virchow-Klinikum
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aMedizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité, Campus Virchow-Klinikum
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aMedizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité, Campus Virchow-Klinikum
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aMedizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité, Campus Virchow-Klinikum
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aMedizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité, Campus Virchow-Klinikum
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bSchering Experimentelle Onkologie, 13353 Berlin, Germany
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aMedizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité, Campus Virchow-Klinikum
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aMedizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité, Campus Virchow-Klinikum
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Thomas Plath
aMedizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité, Campus Virchow-Klinikum
Katharina Detjen
aMedizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité, Campus Virchow-Klinikum
Martina Welzel
aMedizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité, Campus Virchow-Klinikum
Zofia von Marschall
aMedizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité, Campus Virchow-Klinikum
Derek Murphy
aMedizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité, Campus Virchow-Klinikum
Michael Schirner
bSchering Experimentelle Onkologie, 13353 Berlin, Germany
Bertram Wiedenmann
aMedizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité, Campus Virchow-Klinikum
Stefan Rosewicz
aMedizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité, Campus Virchow-Klinikum
Abbreviations used in this paper: Cdk, cyclin-dependent kinase; GAPDH, glyceraldehyde 3-phospate dehydrogenase; MDCK, Madin-Darby canine kidney; PARP, poly(ADP-ribose) polymerase; polyHEMA, polyhydroxyethylmethacrylate; Rb, retinoblastoma protein; TUNEL, terminal deoxynucleotidyl transferase–mediated dUTP biotin nick end labeling.
Received: March 24 2000
Revision Requested: July 24 2000
Accepted: July 24 2000
Online ISSN: 1540-8140
Print ISSN: 0021-9525
© 2000 The Rockefeller University Press
2000
The Rockefeller University Press
J Cell Biol (2000) 150 (6): 1467–1478.
The tumor suppressor gene p16INK4a 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 p16INK4a. We hypothesized that p16INK4a might influence hitherto unknown critical features of a malignant epithelial phenotype, such as anchorage dependence. Here we provide evidence that stable transfection of p16INK4a restitutes apoptosis induction upon loss of anchorage (anoikis) in a variety of human cancer cells. Anoikis in p16INK4a-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. p16INK4a-mediated anoikis was due to selective transcriptional upregulation of the α5 integrin chain of the α5β1 fibronectin receptor as detected by FACS® analysis, immunoprecipitation, Northern blotting, and nuclear run-on assays. Addition of soluble fibronectin and inhibitory α5 antibodies to nonadherent cells completely abolished p16INK4a-mediated anoikis, whereas laminin was ineffective. Furthermore, antisense-induced downregulation of the α5 integrin chain in p16INK4a-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.
© 2000 The Rockefeller University Press
2000
The Rockefeller University Press
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