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Cell Growth & Differentiation Vol. 10, 759-767, November 1999
© 1999 American Association for Cancer Research


Articles

Proteolysis of Heat Shock Transcription Factor Is Associated with Apoptosis in Rat Nb2 Lymphoma Cells1

Mingyu Zhang, Michael J. Blake, Peter W. Gout, Donna J. Buckley and Arthur R. Buckley2

College of Pharmacy [M. Z., D. J. B., A. R. B.] and Department of Molecular and Cellular Physiology [A. R. B.], College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267-0004; Department of Pharmacology and Toxicology, University of North Dakota School of Medicine, Grand Forks, North Dakota 58202 [M. J. B.]; and Department of Cancer Endocrinology, British Columbia Cancer Agency, Vancouver, British Columbia, V5Z 4E6 Canada [P. W. G.]

Abstract

Previously, we reported that prolactin (PRL)-dependent Nb2 lymphoma cells exhibit an aberrant heat shock response because of cysteine protease-mediated fragmentation of the heat shock transcription factor (HSF). Moreover, exposure of the cells to PRL abrogated heat-induced HSF proteolysis. The present study was conducted to investigate whether HSF proteolysis is a component of the apoptotic process in this model. Initially, the effect of heat stress (41°C for 1 h) on apoptosis, determined by agarose gel electrophoresis and flow cytometric analysis, was evaluated in PRL-dependent Nb2-11 cells and in an autonomous subline (Nb2-SFJCD1). Heat was found to induce HSF proteolysis concomitant with activation of apoptosis in each cell line; treatment with PRL blocked these effects. To determine whether HSF proteolysis occurred as a generalized phenomenon associated with apoptosis, the effects of other activators of this process were evaluated. Vinblastine, cycloheximide, and thapsigargin stimulated fragmentation of HSF and hydrolysis of DNA in each cell line. The addition of PRL blocked the effects of vinblastine but was ineffective in cells treated with either cycloheximide or thapsigargin. Iodoacetamide, a cysteine protease inhibitor that blocks HSF fragmentation, also inhibited apoptosis. In addition, Z-VAD, a general caspase antagonist, blocked vinblastine-induced fragmentation of HSF and DNA, suggesting that the enzyme responsible for proteolysis of the transcription factor was likely a caspase family member. The results suggest that proteolysis of HSF reflects the action of one or more caspases activated as a consequence of stimulation of cell death. It is concluded that HSF may represent a previously unrecognized substrate for caspases or other cysteine proteases activated during apoptosis.







HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cell Growth & Differentiation
Copyright © 1999 by the American Association of Cancer Research.