QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online 26 October 2004
doi: 10.1242/jcs.01490

This Article Figures Only Full Text Full Text (PDF) All Versions of this Article: jcs.01490v1 117/24/5815    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in JCS 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 Marconi, A. Articles by Pincelli, C. Search for Related Content PubMed PubMed Citation Articles by Marconi, A. Articles by Pincelli, C.

FLICE/caspase-8 activation triggers anoikis induced by ß₁-integrin blockade in human keratinocytes

Alessandra Marconi^1,*, Paola Atzei^1,*, Cristina Panza¹, Chiara Fila¹, Rossana Tiberio², Francesca Truzzi¹, Tina Wachter³, Martin Leverkus³ and Carlo Pincelli^1,

¹ Institute of Dermatology, University of Modena and Reggio Emilia, Via del Pozzo 71, 41100 Modena, Italy
² Institute of Dermatology, University of Piemonte Orientale, Novara, Italy
³ Department of Dermatology, University of Würzburg Medical School, Josef-Schneider-Str. 2, 97070 Würzburg, Germany

Author for correspondence (e-mail: carlo{at}unimo.it)

Accepted 10 August 2004

ß₁-integrin protects keratinocyte stem cells (KSC) from cell-detachment apoptosis (`anoikis'). Here we show that caspase-8 active protein is detected in both young transit amplifying (TA) cells and TA cells, but not in KSC. On suspension, caspases are activated earlier in young TA than in KSC, whereas anti-ß₁-integrin neutralizing antibody accelerates caspase activation in both KSC and young TA. Caspases 8 and 10 are the first caspases to be activated whereas caspase-8 inhibitor zIETD-fmk delays the activation of Bid, caspase-9 and caspase-3. However, the caspase-9 inhibitor zLEDH-fmk does not block the activation of caspase-8, Bid, caspase-10 and caspase-3. Moreover, caspase-8, but not caspase-9 inhibitor partially prevents keratinocyte anoikis. As FLIP inhibits caspase-8 processing, we retrovirally infected HaCaT keratinocytes with c-FLIP_L. Anti-ß₁-integrin fails to activate caspase-8, Bid, caspase-9 and to induce the release of cytochrome c in c-FLIP_L overexpressing keratinocytes. Finally, overexpression of c-FLIP_L partially prevents anoikis in both suspended and anti-ß₁ integrin-treated cells. Taken together, these results indicate that the extrinsic apoptotic pathway triggered by caspase-8 predominates in keratinocyte anoikis. However, the release of cytochrome c and the later activation of caspase-9 seem to suggest that the intrinsic mitochondrial pathway may intervene as a positive feedback loop of caspase activation.

Key words: Keratinocyte, Anoikis, Integrin, Caspase, cFLIP, Stem cell

Related articles in JCS:

...keratinocyte executioner named

JCS 2004 117: 2404. [Full Text]  

This article has been cited by other articles:

				R. S. Al-Lamki, J. Wang, A. M. Tolkovsky, J. A. Bradley, J. L. Griffin, S. Thiru, E. C.Y. Wang, E. Bolton, W. Min, P. Moore, et al. TL1A Both Promotes and Protects from Renal Inflammation and Injury J. Am. Soc. Nephrol., May 1, 2008; 19(5): 953 - 960. [Abstract] [Full Text] [PDF]

				L. M. Laguinge, R. N. Samara, W. Wang, W. S. El-Deiry, G. Corner, L. Augenlicht, L. Mishra, and J. M. Jessup DR5 Receptor Mediates Anoikis in Human Colorectal Carcinoma Cell Lines Cancer Res., February 1, 2008; 68(3): 909 - 917. [Abstract] [Full Text] [PDF]

				A. Marconi, K. Dallaglio, R. Lotti, C. Vaschieri, F. Truzzi, F. Fantini, and C. Pincelli Survivin Identifies Keratinocyte Stem Cells and Is Downregulated by Anti-{beta}1 Integrin During Anoikis Stem Cells, January 1, 2007; 25(1): 149 - 155. [Abstract] [Full Text] [PDF]

				S. Maubant, D. Saint-Dizier, M. Boutillon, F. Perron-Sierra, P. J. Casara, J. A. Hickman, G. C. Tucker, and E. Van Obberghen-Schilling Blockade of {alpha}vbeta3 and {alpha}vbeta5 integrins by RGD mimetics induces anoikis and not integrin-mediated death in human endothelial cells Blood, November 1, 2006; 108(9): 3035 - 3044. [Abstract] [Full Text] [PDF]

				I. Podgorski and B. F. Sloane Loss of Caspase-8 in Tumor Cells: Mechanism to Overcome Integrin-Mediated Death? Mol. Interv., June 1, 2006; 6(3): 132 - 136. [Abstract] [Full Text] [PDF]

				L. E. Connell and D. M. Helfman Myosin light chain kinase plays a role in the regulation of epithelial cell survival J. Cell Sci., June 1, 2006; 119(11): 2269 - 2281. [Abstract] [Full Text] [PDF]

				Z. Liu, H. Li, M. Derouet, A. Berezkin, T. Sasazuki, S. Shirasawa, and K. Rosen Oncogenic Ras Inhibits Anoikis of Intestinal Epithelial Cells by Preventing the Release of a Mitochondrial Pro-apoptotic Protein Omi/HtrA2 into the Cytoplasm J. Biol. Chem., May 26, 2006; 281(21): 14738 - 14747. [Abstract] [Full Text] [PDF]