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Molecular and Cellular Biology, September 2001, p. 6233-6242, Vol. 21, No. 18
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.18.6233-6242.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Targeting of the c-Abl Tyrosine Kinase to Mitochondria in Endoplasmic Reticulum Stress-Induced Apoptosis

Yasumasa Ito,1 Pramod Pandey,1 Neerad Mishra,2 Shailendra Kumar,1 Navneet Narula,3 Surender Kharbanda,1 Satya Saxena,2 and Donald Kufe1,*

Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 021151; Lovelace Respiratory Research Institute, Albuquerque, New Mexico 871152; and Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-42823

Received 2 March 2001/Returned for modification 4 April 2001/Accepted 15 June 2001

The ubiquitously expressed c-Abl tyrosine kinase localizes to the nucleus and cytoplasm. Using confocal microscopy, we demonstrated that c-Abl colocalizes with the endoplasmic reticulum (ER)-associated protein grp78. Expression of c-Abl in the ER was confirmed by immunoelectron microscopy. Subcellular fractionation studies further indicate that over 20% of cellular c-Abl is detectable in the ER. The results also demonstrate that induction of ER stress with calcium ionophore A23187, brefeldin A, or tunicamycin is associated with translocation of ER-associated c-Abl to mitochondria. In concert with targeting of c-Abl to mitochondria, cytochrome c is released in the response to ER stress by a c-Abl-dependent mechanism, and ER stress-induced apoptosis is attenuated in c-Abl-deficient cells. These findings indicate that c-Abl is involved in signaling from the ER to mitochondria and thereby the apoptotic response to ER stress.

* Corresponding author. Mailing address: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115. Phone: (617) 632-3141. Fax: (617) 632-2934. E-mail: Donald_Kufe{at}dfci.harvard.edu.

Molecular and Cellular Biology, September 2001, p. 6233-6242, Vol. 21, No. 18
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.18.6233-6242.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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