Keratinocytes enriched for stem cells are protected from anoikis via an integrin signaling pathway in a Bcl‐2 dependent manner

Abstract

Because inhibition of integrin signaling induces apoptosis, we investigated whether keratinocytes expressing L L1 and K K6L L4 integrins (enriched for stem cells) are protected from cell death. Keratinocytes rapidly adhering to type IV collagen expressed highest levels of L L1 and K K6L L4 and of the anti-apoptotic stem cell marker p63. Apoptotic cells were signi¢cantly higher in slowly adhering than in rapidly adhering keratinocytes. Anti-L L1 integrin caused a signi¢cant increase in apoptotic cells, while it decreased Bcl-2 levels in stem keratinocytes. Bax and Bad proteins were higher in slowly adhering than in rapidly adhering cells. By contrast, Bcl-2, Bcl-x and Mcl-1 proteins were highest in rapidly adhering keratinocytes and nearly absent in slowly adhering cells. After addition of anti-L L1 integrin, the apoptotic rate was signi¢cantly higher in HaCaT cells not expressing Bcl-2 than in controls. These results indicate that keratinocytes enriched for stem cells are protected from apoptosis via L L1 integrin, in a Bcl-2 dependent manner. ß

The Protective Role of Simvastatin on Methotrexate-Induced Bone Injury in Adult Albino Rat

“…This gene has been reported to prolong the survival of cells by specifically inhibiting apoptosis [46] . Moreover, the Bcl-2 protein plays an important role in preserving stem cells [47]. In the current work, bone sections of the MTX group (Group C) showed strong positive staining for the anti-apoptotic Bcl2 protein that is supposed to be increased in case of bone injury to protect the mesenchymal cells responsible for bone formation in the bone marrow by inhibiting apoptosis.…”

Sca-1 expression identifies stem cells in the proximal region of prostatic ducts with high capacity to reconstitute prostatic tissue

“…The Bcl-2 protein suppresses apoptosis (19) and is present in many long-lived cells (42). Bcl-2 protects hematopoietic and keratinocyte stem cells from apoptotic death (21,43), and over-expression of Bcl-2 increases the numbers of hematopoietic stem cells in vivo (20) and protects hematopoietic stem cells from the harmful effects of a number of chemotherapeutic agents, thus ensuring their survival (44). The expression of Bcl-2 by the prostate stem cell population that has high levels of Sca-1 and significant in vivo proliferative potential is therefore likely to ensure the long-term survival of this cell population.…”

“…We have shown that cells with stem cell features (quiescence and high proliferative potential) are concentrated in the proximal region of prostatic ducts (9). By using FACS analysis, we determined whether the expression of three antigens, Sca-1, ␣6 integrin, and Bcl-2, known to be expressed by stem cells of other origins (10)(11)(12)(13)(14)(15)(16)(17)(18)(20)(21)(22), differs between the proximal and remaining ductal regions.…”

“…␣6 integrin (CD49f) is expressed by primitive cells in the liver (16) and skin (17), and anti-␣6 integrin antibodies have been used to enrich for spermatogonial stem cells from mouse testis (18). Bcl-2, an antiapoptotic protein (19), may protect primitive cells from death and is expressed by hematopoietic, keratinocyte, and colon stem cells (20)(21)(22).…”

Role of the tumor microenvironment in mediating de novo resistance to drugs and physiological mediators of cell death

“…The initiating event of anoikis is not clearly defined. In some cell models Bcl-2 or Bcl-xl can inhibit detachment-induced apoptosis or anokois, suggesting a mitochondria-dependent mechanism (Rytomaa et al, 1999;Coll et al, 2002;Tiberio et al, 2002). Another recent mechanism associated with aniokis is the release of the Bcl-2 family member Bmf from cytoskeletal elements (Puthalakath et al, 2001).…”