Overexpression of Bcl-2 Protects from Ultraviolet B-Induced Apoptosis but Promotes Hair Follicle Regression and Chemotherapy-Induced Alopecia

Abstract

Hair follicle (HF) growth and regression is an exquisitely regulated process of cell proliferation followed by massive cell death and is accompanied by cyclical expression of the apoptosis regulatory gene pair, Bcl-2 and Bax. To further investigate the role of Bcl-2 expression in the control of hair growth and keratinocyte apoptosis, we have used transgenic mice that overexpress human Bcl-2 in basal epidermis and in the outer root sheath under the control of the human keratin-14 promoter (K14/Bcl-2). When irradiated with ultraviolet B (UVB) light, K14/Bcl-2 mice developed about 5-10-fold fewer sunburn cells (ie, apoptotic keratinocytes) in the basal layer of the epidermis, compared to wild-type mice, whereas cultures of primary keratinocytes from transgenic mice were completely resistant to UVB-induced histone formation, at doses that readily induced histone release from wild-type cells. K14/Bcl-2 mice show no alteration of neonatal hair follicle morphogenesis or of the onset of the first wave of HF regression (catagen). However, compared to wild-type controls, K14/Bcl-2 mice subsequently displayed a significant acceleration of spontaneous catagen progression. During chemotherapy-induced alopecia, follicular dystrophy was promoted in K14/Bcl-2 mice. Thus, although K14-driven overexpression of Bcl-2 protected murine epidermal keratinocytes from UVB-induced apoptosis, it surprisingly promoted catagen- and chemotherapy-associated keratinocyte apoptosis.

An Investigation of Apoptosis in Androgenetic Alopecia

“…When bcl-2 overexpression was studied in outer root sheath keratinocytes in transgenic mice treated with cyclophosphamide, increased catagen induction was observed [15,16]. Specific catagen-promoting factors were not identified, however.…”

“…Specific catagen-promoting factors were not identified, however. As one of the regulators of the hair cycle [3] and a promoter of catagen, FGF-5 was suggested, though not proven [16].…”

Death penalty for keratinocytes: apoptosis versus cornification

“…Skin-specific bcl-2 transgenesis induces acceleration of the first anagen phase. 101 In these mice, keratinocyte differentiation is not affected, but upon exposure to UV light fewer apoptotic cells are observed. 101 These data indicate that Bcl-2 is important for keratinocyte apoptosis, but not for keratinocyte cornification.…”

“…101 In these mice, keratinocyte differentiation is not affected, but upon exposure to UV light fewer apoptotic cells are observed. 101 These data indicate that Bcl-2 is important for keratinocyte apoptosis, but not for keratinocyte cornification. Epidermal specific overexpression of the antiapoptotic Bcl-X L and proapoptotic Bcl-X S , respectively, decreased and increased sensitivity towards apoptosis induced by UVB, 102 but general epidermal formation was not affected in these animals.…”

Programmed cell death in the skin

“…The Bcl-2 knock-out mice show a prolonged growth phase, while transgenic mice show acceleration of this phase (Muller-Rover et al, 2000;Veis et al, 1993). Also hair graying occurs through apoptosis of melanocytes in the involution phase, driven by pro-apoptotic Bim (Bouillet et al, 2001).…”