Survivin identifies keratinocyte stem cells and it is down-regulated by anti- 1 integrin during anoikis

¹ Department of Medicine, Institute of Dermatology, University of Modena and Reggio Emilia, Modena, Italy

^* To whom correspondence should be addressed. E-mail: carlo{at}unimo.it.

	Abstract

Survivin belongs to the family of inhibitor of apoptosis proteins (IAP) and it is involved in regulation of cell death as well as cell division. Here we show that wild- type (WT) survivin is expressed in a subpopulation of basal keratinocytes in normal human skin, at the cytoplasmic level. WT-survivin is highly expressed in keratinocyte stem cells (KSC), while its mRNA level decreases in transit amplifying (TA) cells and disappears in postmitotic (PM) cells. Similarly, WT-survivin protein is expressed in KSC, almost undetectable in TA and absent in PM cells. Real Time PCR demonstrates that the putative anti-apoptotic isoforms survivin-2B and survivin-Ex3 are expressed at highest levels in KSC, while they tend to decrease in TA cells and disappear in PM. On the contrary, the putative pro-apoptotic variants of survivin, survivin-3B and survivin-2 tend to be high in PM and TA and almost absent in KSC. By confocal microscopy, survivin is predominantly expressed at the nuclear level in KSC, that proliferate significantly better than TA, which, in turn, express mostly cytosolic survivin WT. Blocking 1 integrin signal down-regulates WT-survivin mRNA and protein expression and induces apoptosis (anoikis) in KSC. On the other hand, inhibition of 1 integrin up-regulates mRNA expression of survivin-2. Taken together, these results indicate that survivin identifies human KSC. Expression of nuclear survivin could reflect the different behavior between KSC in vitro and in vivo, in terms of proliferation. Finally, survivin could be part of the "niche" protection by preventing anoikis in KSC.