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Mcl-1 functions as major epidermal survival protein required for proper keratinocyte differentiation.
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| Author |
Leonid A Sitailo, Anita Jerome-Morais, Mitchell F Denning |
| Citation Information |
The Journal of investigative dermatology, 129:1351-60 (2009) |
| Keywords |
Apoptosis, Caspase 3, Cell Culture Techniques, Cell Differentiation, Cell Line, Tumor, Cell Survival, Enzyme Activation, Enzyme Inhibitors, Epidermis, Gene Expression Regulation, Humans, Keratinocytes, Proto-Oncogene Proteins c-bcl-2, RNA Interference, Skin |
| Related Products |
S7100 |
| Pub Med ID |
19037233 |
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Rapid downregulation of the antiapoptotic Bcl-2 family protein myeloid cell leukemia 1 (Mcl-1) is required for UV-induced apoptosis, underlining an important role for Mcl-1 in epidermal pathology. To determine if Mcl-1 has a specific role in normal keratinocyte (KC) biology, Mcl-1 was downregulated in human KCs by RNAi and these KCs were induced to differentiate in organotypic raft cultures. Mcl-1 shRNA organotypic cultures showed increased levels of spontaneous premature apoptosis, implicating Mcl-1 as an essential KC survival protein. Mcl-1-downregulated cultures also had reduced granular and cornified layers, and produced lower levels of cross-linked protein and cornified envelopes. Cornification could only partially be rescued with the general caspase inhibitor z-VAD, suggesting that reduced cornification was not entirely because of premature apoptosis. Differentiation markers (K1, K10, filaggrin, loricrin, cleaved caspase-14) were normally expressed in control organotypic cultures, but were expressed at reduced levels in organotypic cultures with downregulated Mcl-1. The defect in differentiation marker expression was independent of apoptosis as it could not be rescued by z-VAD. Thus, Mcl-1 serves two important, independent functions in epidermal KCs: acting as a major survival protein by inhibiting premature apoptosis in the spinous and granular layers to promote conification, and promoting the robust induction of KC differentiation markers.
