This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yang, X. Articles by Zhang, H.-G. Search for Related Content PubMed PubMed Citation Articles by Yang, X. Articles by Zhang, H.-G.

(American Journal of Pathology. 2005;167:705-719.)
© 2005 American Society for Investigative Pathology

Cleavage of p53-Vimentin Complex Enhances Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Mediated Apoptosis of Rheumatoid Arthritis Synovial Fibroblasts

Xinwen Yang^*, Jianhua Wang^*, Cunren Liu^*, William E. Grizzle, Shaohua Yu^*, Shuangqin Zhang^*, Stephen Barnes, William J. Koopman^*, John D. Mountz^*, Robert P. Kimberly^* and Huang-Ge Zhang^*

From the Department of Medicine,^* Division of Clinical Immunology and Rheumatology, and the Departments of Pathology and Pharmacology, University of Alabama at Birmingham, Birmingham; and the Birmingham Veterans Administration Medical Center, Birmingham, Alabama

Rheumatoid arthritis synovial fibroblasts (RASFs) contribute to arthritic cartilage degradation. Although RASFs are normally resistant to apoptosis, Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-based gene therapy has been successfully used in a mouse model of arthritis. We investigated this further by treating human RASFs with nontoxic doses of the proteasome inhibitor lactacystin. Treatment induced cytosolic accumulation of p53 and enhanced the susceptibility of RASFs to apoptosis mediated by TRAIL-R2 (DR5) but not Fas. A specific role for p53 in TRAIL-R2-mediated apoptosis was indicated by the ability of p53 siRNA to significantly reduce RASF apoptosis and by the reduced apoptosis of RASFs bearing p53 mutations on treatment with anti-DR5 antibody or anti-DR5 antibody plus lactacystin. p53 immunoprecipitation followed by mass spectrometry identified a vimentin-p53 complex, an interaction that was confirmed by reciprocal vimentin-p53 immunoprecipitation and by co-immunofluorescence. Interestingly, human caspase-4 cleaved human vimentin, and blockade of caspase-4 with a chemical inhibitor or with specific siRNA significantly inhibited TRAIL-R2-mediated apoptosis of RASFs. Furthermore, blockade of caspase-4 was paralleled by persistence of a cytosolic pattern of p53 and absence of p53 translocation to the nucleus. Taken together, our findings suggest a unique role for caspase-4 in cleaving vimentin and releasing cytosolic p53 for nuclear translocation, events that may regulate the sensitivity of RASFs to receptor-mediated apoptosis.

This article has been cited by other articles:

				F. Bossi, L. Rizzi, R. Bulla, A. Debeus, C. Tripodo, P. Picotti, E. Betto, P. Macor, C. Pucillo, R. Wurzner, et al. C7 is expressed on endothelial cells as a trap for the assembling terminal complement complex and may exert anti-inflammatory function Blood, April 9, 2009; 113(15): 3640 - 3648. [Abstract] [Full Text] [PDF]

				S. Kim and P. A. Coulombe Intermediate filament scaffolds fulfill mechanical, organizational, and signaling functions in the cytoplasm Genes & Dev., July 1, 2007; 21(13): 1581 - 1597. [Abstract] [Full Text] [PDF]

				J. Wang, C. Li, Y. Liu, W. Mei, S. Yu, C. Liu, L. Zhang, X. Cao, R. P. Kimberly, W. Grizzle, et al. JAB1 Determines the Response of Rheumatoid Arthritis Synovial Fibroblasts to Tumor Necrosis Factor-{alpha} Am. J. Pathol., September 1, 2006; 169(3): 889 - 902. [Abstract] [Full Text] [PDF]

				H.-G. Zhang, C. Liu, K. Su, S. Yu, L. Zhang, S. Zhang, J. Wang, X. Cao, W. Grizzle, and R. P. Kimberly A Membrane Form of TNF-{alpha} Presented by Exosomes Delays T Cell Activation-Induced Cell Death. J. Immunol., June 15, 2006; 176(12): 7385 - 7393. [Abstract] [Full Text] [PDF]