|
|
 Previous Article | Table of Contents | Next Article 
Blood, 1 September 2001, Vol. 98, No. 5, pp. 1532-1541
NEOPLASIA
Adhesion to fibronectin selectively protects Bcr-Abl+
cells from DNA damage-induced apoptosis
Heiko van der Kuip,
Alexander W. Goetz,
Cornelius Miething,
Justus Duyster, and
Walter E. Aulitzky
From the Dr Margarete Fischer-Bosch Institute for
Clinical Pharmacology, Stuttgart, Germany; Department of Internal
Medicine, Oncology and Hematology, Robert Bosch Hospital, Stuttgart,
Germany; and Department of Internal Medicine III, Technical University
of Munich, Germany.
The phenotype of Bcr-Abl-transformed cells is characterized by a
growth factor-independent survival and a reduced susceptibility to
apoptosis. Furthermore, Bcr-Abl kinase alters adhesion features by
phosphorylating cytoskeletal and/or signaling proteins important for
integrin function. Integrin-mediated adhesion to extracellular matrix
molecules is critical for the regulation of growth and apoptosis.
However, effects of integrin signaling on regulation of apoptosis in
cells expressing Bcr-Abl are largely unknown. The influence of adhesion
on survival and apoptosis in Bcr-Abl+ and
Bcr-Abl BaF3 cells was investigated.
p185bcr-abl-transfected BaF3 cells preadhered to
immobilized fibronectin had a significant survival advantage and
reduced susceptibility to apoptosis following  -irradiation when
compared with the same cells grown on laminin, on polylysin, or in
suspension. Both inhibition of Bcr-Abl kinase by STI571 and inhibition
of specific adhesion reversed the fibronectin-mediated antiapoptotic
effect in BaF3p185. The DNA damage response of Bcr-Abl
BaF3 cells was not affected by adhesion to fibronectin. In contrast to
parental BaF3 cells, BaF3p185 adherent to fibronectin did not release cytochrome c to the cytosol following irradiation.
The fibronectin-mediated antiapoptotic mechanism in Bcr-Abl-active cells was not mediated by overexpression of Bcl-XL or Bcl-2
but required an active phosphatidylinositol 3-kinase (PI-3K).
Kinase-active Bcr-Abl in combination with fibronectin-induced integrin
signaling led to a hyperphosphorylation of AKT. Thus, cooperative
activation of PI-3K/AKT by Bcr-Abl and integrins causes synergistic
protection of Bcr-Abl+ cells from DNA damage-induced apoptosis.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
Y. Canitrot, R. Falinski, T. Louat, G. Laurent, C. Cazaux, J.-S. Hoffmann, D. Lautier, and T. Skorski
p210 BCR/ABL kinase regulates nucleotide excision repair (NER) and resistance to UV radiation
Blood,
October 1, 2003;
102(7):
2632 - 2637.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Wohlbold, H. van der Kuip, C. Miething, H.-P. Vornlocher, C. Knabbe, J. Duyster, and W. E. Aulitzky
Inhibition of bcr-abl gene expression by small interfering RNA sensitizes for imatinib mesylate (STI571)
Blood,
September 15, 2003;
102(6):
2236 - 2239.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. A. Wertheim, K. Forsythe, B. J. Druker, D. Hammer, D. Boettiger, and W. S. Pear
BCR-ABL-induced adhesion defects are tyrosine kinase-independent
Blood,
May 13, 2002;
99(11):
4122 - 4130.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Sonoyama, I. Matsumura, S. Ezoe, Y. Satoh, X. Zhang, Y. Kataoka, E. Takai, M. Mizuki, T. Machii, H. Wakao, et al.
Functional Cooperation among Ras, STAT5, and Phosphatidylinositol 3-Kinase Is Required for Full Oncogenic Activities of BCR/ABL in K562 Cells
J. Biol. Chem.,
March 1, 2002;
277(10):
8076 - 8082.
[Abstract]
[Full Text]
[PDF]
|
|
|
| |
