RESEARCH ARTICLE


Lipid Rafts and Keratinocyte Apoptosis: Regulation via Death Receptors and Akt



Robert Gniadecki*, 1, Yves Poumay2
1 1Department of Dermatology, University of Copenhagen, Bispebjerg Hospital, Bispebjerg Bakke 23, 2400 Copenhagen NV, Denmark
2 2Cell and Tissue Laboratory, URPHYM, Faculty of Medicine, University of Namur, 5000 Namur, Belgium


Article Metrics

CrossRef Citations:
0
Total Statistics:

Full-Text HTML Views: 32
Abstract HTML Views: 442
PDF Downloads: 190
Total Views/Downloads: 664
Unique Statistics:

Full-Text HTML Views: 29
Abstract HTML Views: 253
PDF Downloads: 140
Total Views/Downloads: 422



© 2009 Gniadecki and Poumay

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

* Address correspondence to this author at the Department of Dermatology, University of Copenhagen, Bispebjerg Hospital, Bispebjerg Bakke 23, 2400 Copenhagen NV, Denmark; Tel: (+45) 35313165; Fax: (+45) 35315050; E-mail:rg01@bbh.regionh.dk


Abstract

Lipid rafts are cholesterol-rich plasma membrane domains that regulate signal transduction. Lipid rafts can be disrupted by perturbing cholesterol metabolism, either by inhibition of cholesterol synthesis (e.g. by statins), by cholesterol sequestration or removal from the membrane (e.g. by methyl-β-cyclodextrin or filipin III) or by substitution with cholesterol derivatives, which do not support raft assembly (e.g. 5-cholestene 5-β-ol). Work performed in our laboratories as well as by others documented that lipid raft disruption precipitates classic apoptosis in normal and transformed keratinocytes and inhibited cell proliferation. Two mechanisms seem to play a particularly important role. One is mediated via the membrane death receptors such as Fas and TRAIL. Cholesterol depletion causes a ligandindependent activation of these receptors and activation of caspases. The other is mediated via the survival kinase Akt. Raft disruption causes a rapid inhibition of Akt via dephospphorylation of the regulatory sites Thr308 and Ser473. The mechanism of this was the abrogation the binding of Akt and the major Akt kinase, PDK-1 to the membrane via pleckstrin homology (PH) domains. Diminished Akt activity results in deactivation of mTOR, activation of FoxO3a and an increased sensitivity to apoptotic stimuli. Thus, the integrity of lipid rafts is required for the activity of Akt and cell survival and may serve as a potential pharmacological target in the treatment of epidermal cancers.