Apoptosis in the Hair Follicle
2006; Elsevier BV; Volume: 126; Issue: 2 Linguagem: Inglês
10.1038/sj.jid.5700007
ISSN1523-1747
AutoresNatalia V. Botchkareva, Gurpreet S. Ahluwalia, Douglas Shander,
Tópico(s)Dermatologic Treatments and Research
ResumoApoptosis plays an important role in many physiological processes, ranging from morphogenetic events to adult tissue homeostasis, and defects in its regulation contribute to many disorders. Here we review molecular mechanisms of apoptosis in the hair follicle (HF), whose cyclical growth pattern is repeatedly interrupted by apoptosis-driven involution (catagen). We review the common mechanisms underlying apoptosis in the HF during catagen, as well as differences in the regulation of apoptosis between distinct HF cell populations. An overview is provided on the expression and function of molecules involved in the control of various phases of the apoptotic process during catagen. Apoptosis plays an important role in many physiological processes, ranging from morphogenetic events to adult tissue homeostasis, and defects in its regulation contribute to many disorders. Here we review molecular mechanisms of apoptosis in the hair follicle (HF), whose cyclical growth pattern is repeatedly interrupted by apoptosis-driven involution (catagen). We review the common mechanisms underlying apoptosis in the HF during catagen, as well as differences in the regulation of apoptosis between distinct HF cell populations. An overview is provided on the expression and function of molecules involved in the control of various phases of the apoptotic process during catagen. hair follicle inhibitor of apoptosis protein keratinocyte transforming growth factor-β tumor necrosis factor-α Apoptosis is a process of eliminating cells that have fulfilled their biological function during development and tissue homeostasis in multicellular organisms. During the last decade, substantial progress was achieved in the delineation of molecular mechanisms involved in the realization of apoptosis. As an energy-demanding process, apoptosis is initiated by a variety of stimuli, including a withdrawal of growth factors, loss of cell adhesion, stimulation of proapoptotic receptors, or DNA damage (reviewed by Afford and Randhawa, 2000Afford S. Randhawa S. Apoptosis.Mol Pathol. 2000; 53: 55-63Crossref PubMed Scopus (151) Google Scholar). The hair follicle (HF) is a cutaneous organ that shows cyclic activity in postnatal life and transits through periods of active hair growth (anagen), apoptosis-driven involution (catagen), hair shedding (exogen), and relative resting (telogen) (Paus and Cotsarelis, 1999Paus R. Cotsarelis G. The biology of hair follicles.N Engl J Med. 1999; 341: 491-498Crossref PubMed Scopus (883) Google Scholar; Cotsarelis and Millar, 2001Cotsarelis G. Millar S.E. Towards a molecular understanding of hair loss and its treatment.Trends Mol Med. 2001; 7: 293-301Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar; Stenn and Paus, 2001Stenn K.S. Paus R. Controls of hair follicle cycling.Physiol Rev. 2001; 81: 449-494Crossref PubMed Scopus (1033) Google Scholar). During HF growth and hair production, the activity of factors promoting the proliferation, differentiation, and survival predominates, whereas HF regression is characterized by the activation of a variety of signaling pathways that induce apoptosis in HF cells (Lindner et al., 1997Lindner G. Botchkarev V.A. Botchkareva N.V. Ling G. van der Veen C. Paus R. et al.Analysis of apoptosis during hair follicle regression (catagen).Am J Pathol. 1997; 151: 1601-1617PubMed Google Scholar; Soma et al., 1998Soma T. Ogo M. Suzuki J. Takahashi T. Hibino T. Analysis of apoptotic cell death in human hair follicles in vivo and in vitro.J Invest Dermatol. 1998; 111: 948-954Crossref PubMed Scopus (111) Google Scholar; Stenn and Paus, 2001Stenn K.S. Paus R. Controls of hair follicle cycling.Physiol Rev. 2001; 81: 449-494Crossref PubMed Scopus (1033) Google Scholar). This review focuses on the molecular mechanisms of apoptosis in the HF during its physiological involution; mechanisms of apoptosis underlying the distinct hair loss conditions have been reviewed elsewhere (Botchkarev, 2003Botchkarev V.A. Molecular mechanisms of chemotherapy-induced hair loss.J Investig Dermatol Symp Proc. 2003; 8: 72-75Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar; Cotsarelis and Millar, 2001Cotsarelis G. Millar S.E. Towards a molecular understanding of hair loss and its treatment.Trends Mol Med. 2001; 7: 293-301Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar; Hendrix et al., 2005Hendrix S. Handjiski B. Peters E.M. Paus R. A guide to assessing damage response pathways of the hair follicle: lessons from cyclophosphamide-induced alopecia in mice.J Invest Dermatol. 2005; 125: 42-51Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar). Morphologically, apoptosis is characterized by cell shrinkage, membrane blebbing, nuclear condensation, and cellular fragmentation, followed by the formation and the phagocytosis of apoptotic bodies. The process of apoptosis can be divided into four stages: initiation, intracellular response, cell fragmentation, and phagocytosis (reviewed by Afford and Randhawa, 2000Afford S. Randhawa S. Apoptosis.Mol Pathol. 2000; 53: 55-63Crossref PubMed Scopus (151) Google Scholar). The extrinsic apoptotic pathway is activated by binding of specific ligands to the members of the ‘death domain’ family of membrane receptors (Curtin and Cotter, 2003Curtin J.F. Cotter T.G. Live or let die: regulatory mechanisms in Fas-mediated apoptosis.Cell Signal. 2003; 15: 983-992Crossref PubMed Scopus (164) Google Scholar) (Figure 1). All death receptors have an extracellular cysteine-rich domain that is required for ligand binding and an intracellular domain essential for signal transduction (Peter and Krammer, 2003Peter M.E. Krammer P.H. The CD95(Apo-1/Fas) DISC and beyond.Cell Death Differ. 2003; 10: 26-35Crossref PubMed Scopus (868) Google Scholar). Signaling via death receptors results in the recruitment of several intracellular adapter molecules specific for each apoptotic receptor (Fas-associated death domain protein, tumor necrosis factor (TNF) receptor 1–associated death domain, receptor-interacting protein 1, and so on; see Figure 1), all of which contain the death effector domains required for the interaction with similar domains of procaspase-8 and procaspase-10 (Curtin and Cotter, 2003Curtin J.F. Cotter T.G. Live or let die: regulatory mechanisms in Fas-mediated apoptosis.Cell Signal. 2003; 15: 983-992Crossref PubMed Scopus (164) Google Scholar; Roux and Barker, 2002Roux P.P. Barker P.A. Neurotrophin signaling through the p75 neurotrophin receptor.Prog Neurobiol. 2002; 67: 203-233Crossref PubMed Scopus (560) Google Scholar). Activation of caspase-8 and caspase-10 results in their recruitment into the death-inducing signaling complex, followed by activation of caspase-3 along the common apoptotic pathway (Peter and Krammer, 2003Peter M.E. Krammer P.H. The CD95(Apo-1/Fas) DISC and beyond.Cell Death Differ. 2003; 10: 26-35Crossref PubMed Scopus (868) Google Scholar). Caspase-8 may also activate the cytoplasmic protein Bid, which, after its translocation to the mitochondria, induces release of cytochrome c, thus linking the extrinsic and intrinsic apoptotic pathways (Schultz and Harrington, 2003Schultz D.R. Harrington W.J. Apoptosis: programmed cell death at a molecular level.Semin Arthritis Rheum. 2003; 32: 345-369Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar). The intrinsic pathway of apoptosis is activated by a variety of intracellular events that lead to the release of cytochrome c from the mitochondria. This process is controlled by proteins of the Bcl-2 family, which are divided into two groups: inhibitors of apoptosis (for example, Bcl-2, Bcl-xL, and Mcl-1) and promoters of apoptosis (for example, Bax, Bak, Bok, Bcl-xS, Bik, Bim, Bad, and Bid) (van Gurp et al., 2003van Gurp M. Festjens N. van Loo G. Saelens X. Vandenabeele P. Mitochondrial intermembrane proteins in cell death.Biochem Biophys Res Commun. 2003; 304: 487-497Crossref PubMed Scopus (338) Google Scholar). Bim, Bad, and Bid may act as sensors for cellular integrity and the growth factor supply. Bim serves as a sensor of cytoskeleton integrity, and its proapoptotic activity is regulated by interaction with the dynein motor complex (Puthalakath et al., 1999Puthalakath H. Huang D.C. O'Reilly L.A. King S.M. Strasser A. The pro-apoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex.Mol Cell. 1999; 3: 287-296Abstract Full Text Full Text PDF PubMed Scopus (891) Google Scholar). Bad operates as a sensor for growth factor withdrawal, as deprivation of survival growth factors induces Bad dephosphorylation, which results in apoptosis (Chiang et al., 2001Chiang C.W. Harris G.E.C. Masters S.C. Subramanian R. Shenolikar S. Wadzinski B.E. et al.Protein phosphatase 2A activates the proapoptotic function of BAD in interleukin-3-dependent lymphoid cells by a mechanism requiring 14-3-3 dissociation.Blood. 2001; 97: 1289-1297Crossref PubMed Scopus (131) Google Scholar). The cytoplasmic protein Bid may be cleaved by caspase-8, granzyme B, and cathepsin into a truncated isoform (tBid), which, after translocation to the mitochondria, promotes cytochrome c release and apoptosis (van Gurp et al., 2003van Gurp M. Festjens N. van Loo G. Saelens X. Vandenabeele P. Mitochondrial intermembrane proteins in cell death.Biochem Biophys Res Commun. 2003; 304: 487-497Crossref PubMed Scopus (338) Google Scholar). After its release into the cytoplasm, cytochrome c recruits the caspase adapter molecule Apaf-1 and the apoptosis initiator enzyme procaspase-9, which together form a holoenzyme complex called an apoptosome (van Gurp et al., 2003van Gurp M. Festjens N. van Loo G. Saelens X. Vandenabeele P. Mitochondrial intermembrane proteins in cell death.Biochem Biophys Res Commun. 2003; 304: 487-497Crossref PubMed Scopus (338) Google Scholar). Apoptosomes promote the formation of the active form of caspase-3 along the common pathway of apoptosis (Figure 1). Caspase-3 activation may be inhibited by members of the inhibitor of apoptosis protein (IAP) family, which are located in the cytosol and prevent the activation of procaspases. However, during apoptosis the inhibitory activity of IAPs is neutralized by Smac/DIABLO protein, which is released from the mitochondria and is capable of sequestering IAPs (van Gurp et al., 2003van Gurp M. Festjens N. van Loo G. Saelens X. Vandenabeele P. Mitochondrial intermembrane proteins in cell death.Biochem Biophys Res Commun. 2003; 304: 487-497Crossref PubMed Scopus (338) Google Scholar; Riedl and Shi, 2004Riedl S.J. Shi Y. Molecular mechanisms of caspase regulation during apoptosis.Nat Rev Mol Cell Biol. 2004; 5: 897-907Crossref PubMed Scopus (1470) Google Scholar). Both extrinsic and intrinsic apoptotic pathways result in the activation of caspase-3, which is believed to be the key proteolytic enzyme capable of cleaving a large variety of intracellular substrates. These include structural and signaling proteins, transcription factors, and regulators of DNA repair and RNA metabolism (Shi, 2002Shi Y. Mechanisms of caspase activation and inhibition during apoptosis.Mol Cell. 2002; 9: 459-470Abstract Full Text Full Text PDF PubMed Scopus (1358) Google Scholar). In addition, caspase-3 cleaves caspase-activated deoxyribonuclease, which translates into the nucleus and initiates DNA cleavage (van Gurp et al., 2003van Gurp M. Festjens N. van Loo G. Saelens X. Vandenabeele P. Mitochondrial intermembrane proteins in cell death.Biochem Biophys Res Commun. 2003; 304: 487-497Crossref PubMed Scopus (338) Google Scholar). These processes result in the appearance of the degraded chromatin fragments, lysosomes, mitochondria, and other degenerated cell organelles covered by cell membrane, which are morphologically distinguishable as apoptotic bodies (Afford and Randhawa, 2000Afford S. Randhawa S. Apoptosis.Mol Pathol. 2000; 53: 55-63Crossref PubMed Scopus (151) Google Scholar; Shi, 2002Shi Y. Mechanisms of caspase activation and inhibition during apoptosis.Mol Cell. 2002; 9: 459-470Abstract Full Text Full Text PDF PubMed Scopus (1358) Google Scholar). During the final steps of apoptosis, cellular, and nuclear fragmentation is also accompanied by changes in the cell membrane and by the translocation of phosphatidylserine from the inner to the outer portion of the cell membrane, leading to its recognition by neighboring cells, macrophages, or dendritic cells and then to its phagocytosis (Fadok, 1999Fadok V.A. Clearance: the last and often forgotten stage of apoptosis.J Mammary Gland Biol Neoplasia. 1999; 4: 203-211Crossref PubMed Scopus (67) Google Scholar; Afford and Randhawa, 2000Afford S. Randhawa S. Apoptosis.Mol Pathol. 2000; 53: 55-63Crossref PubMed Scopus (151) Google Scholar; Schultz and Harrington, 2003Schultz D.R. Harrington W.J. Apoptosis: programmed cell death at a molecular level.Semin Arthritis Rheum. 2003; 32: 345-369Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar). CD14, CD36, CD68, the class A scavenger receptors and the vitronectin receptor expressed by macrophages are all capable of interaction with several molecular determinants expressed on apoptotic cells, including anionic phospholipids, phosphatidylserine, and ICAM-3 (Afford and Randhawa, 2000Afford S. Randhawa S. Apoptosis.Mol Pathol. 2000; 53: 55-63Crossref PubMed Scopus (151) Google Scholar). In addition, serum proteins such as β2-glycoprotein and the complement component C1q can bind to apoptotic cells and enhance their uptake by macrophages (Kagan et al., 2003Kagan V.E. Borisenko G.G. Serinkan B.F. Tyurina Y.Y. Tyurin V.A. Jiang J. et al.Appetizing rancidity of apoptotic cells for macrophages: oxidation, externalization, and recognition of phosphatidylserine.Am J Physiol Lung Cell Mol Physiol. 2003; 285: L1-L17Crossref PubMed Scopus (33) Google Scholar). Although catagen is often thought of as a regressive event, it is an exquisitely orchestrated energy-requiring remodeling process, whose progression assures renewal of further generation of HFs. Catagen was first characterized in detail by Kligman and by Straile et al. (Kligman, 1959Kligman A.M. The human hair cycle.J Invest Dermatol. 1959; 33: 307-316Crossref PubMed Scopus (219) Google Scholar; Straile et al., 1961Straile W.Z. Chase H.B. Arsenault C. Growth and differentiation of hair follicles between activity and quiescence.J Exp Zool. 1961; 148: 205-222Crossref PubMed Scopus (93) Google Scholar). It lasts about 2–3 weeks in humans and 3 days in mice (Kligman, 1959Kligman A.M. The human hair cycle.J Invest Dermatol. 1959; 33: 307-316Crossref PubMed Scopus (219) Google Scholar; Parakkal, 1970Parakkal P.F. Morphogenesis of the hair follicle during catagen.Z Zellforsch Mikrosk Anat. 1970; 107: 174-186Crossref PubMed Scopus (36) Google Scholar; Straile et al., 1961Straile W.Z. Chase H.B. Arsenault C. Growth and differentiation of hair follicles between activity and quiescence.J Exp Zool. 1961; 148: 205-222Crossref PubMed Scopus (93) Google Scholar). Morphologically and functionally, catagen is divided into eight substages, each characterized by distinct patterns of apoptosis (Müller-Röver et al., 2001Müller-Röver S. Handjiski B. van der Veen C. Eichmuller S. Foitzik K. McKay I.A. et al.A comprehensive guide for the accurate classification of murine hair follicles in distinct hair cycle stages.J Invest Dermatol. 2001; 117: 3-15Crossref PubMed Google Scholar) (Figure 2a). During the murine hair cycle, apoptotic cells visualized by TUNEL staining first appear in the melanogenic area of the late-anagen HF (Tobin et al., 1998Tobin D.J. Hagen E. Botchkarev V.A. Paus R. Do hair bulb melanocytes undergo apoptosis during hair follicle regression (catagen)?.J Invest Dermatol. 1998; 111: 941-947Crossref PubMed Scopus (111) Google Scholar). In early-catagen HFs, apoptotic cells are seen in the HF matrix; later, TUNEL+ cells are seen in the outer and inner root sheaths (mid- and late catagen) and are then abundant in the epithelial strand (late catagen) (Lindner et al., 1997Lindner G. Botchkarev V.A. Botchkareva N.V. Ling G. van der Veen C. Paus R. et al.Analysis of apoptosis during hair follicle regression (catagen).Am J Pathol. 1997; 151: 1601-1617PubMed Google Scholar; Matsuo et al., 1998Matsuo K. Mori O. Hashimoto T. Apoptosis in murine hair follicles during catagen regression.Arch Dermatol Res. 1998; 290: 133-136Crossref PubMed Scopus (16) Google Scholar). In advanced catagen stages, TUNEL+ cells are also present in the club hair and in the bulge (Lindner et al., 1997Lindner G. Botchkarev V.A. Botchkareva N.V. Ling G. van der Veen C. Paus R. et al.Analysis of apoptosis during hair follicle regression (catagen).Am J Pathol. 1997; 151: 1601-1617PubMed Google Scholar; Ito et al., 2004Ito M. Kizawa K. Hamada K. Cotsarelis G. Hair follicle stem cells in the lower bulge form the secondary germ, a biochemically distinct but functionally equivalent progenitor cell population, at the termination of catagen.Differentiation. 2004; 72: 548-557Crossref PubMed Scopus (176) Google Scholar). However, apoptotic cells are never seen in the dermal papilla of catagen HFs in humans and mice under physiological conditions (Lindner et al., 1997Lindner G. Botchkarev V.A. Botchkareva N.V. Ling G. van der Veen C. Paus R. et al.Analysis of apoptosis during hair follicle regression (catagen).Am J Pathol. 1997; 151: 1601-1617PubMed Google Scholar; Matsuo et al., 1998Matsuo K. Mori O. Hashimoto T. Apoptosis in murine hair follicles during catagen regression.Arch Dermatol Res. 1998; 290: 133-136Crossref PubMed Scopus (16) Google Scholar; Soma et al., 1998Soma T. Ogo M. Suzuki J. Takahashi T. Hibino T. Analysis of apoptotic cell death in human hair follicles in vivo and in vitro.J Invest Dermatol. 1998; 111: 948-954Crossref PubMed Scopus (111) Google Scholar). Therefore, the spatio-temporal distribution of TUNEL+ cells in the HF during catagen may be considered as a ‘wave’ starting from the melanogenic area (late anagen), propagating to the hair matrix (early catagen) and then to the proximal/central outer and inner root sheaths and hair shaft (mid- and late catagen). Distinct cell populations in the HF possess differential susceptibility to apoptosis. The most susceptible to apoptosis are the majority of the follicular epithelial cells and melanocytes, whereas dermal papilla fibroblasts, and some of the keratinocytes (KCs) and melanocytes selected for survival, are resistant to apoptosis (Lindner et al., 1997Lindner G. Botchkarev V.A. Botchkareva N.V. Ling G. van der Veen C. Paus R. et al.Analysis of apoptosis during hair follicle regression (catagen).Am J Pathol. 1997; 151: 1601-1617PubMed Google Scholar; Seiberg et al., 1995Seiberg M. Marthinuss J. Stenn K.S. Changes in expression of apoptosis-associated genes in skin mark early catagen.J Invest Dermatol. 1995; 104: 78-82Crossref PubMed Scopus (85) ; Tobin et al., 1998Tobin D.J. Hagen E. Botchkarev V.A. Paus R. Do hair bulb melanocytes undergo apoptosis during hair follicle regression (catagen)?.J Invest Dermatol. 1998; 111: 941-947Crossref PubMed Scopus (111) Google Scholar). Apoptotic cells in the HF are phagocytosed by macrophages and by neighboring epithelial cells, which fill the space left by apoptotic cells (the “apoptotic force” hypothesis introduced by K. Stenn (Stenn and Paus, 2001Stenn K.S. Paus R. Controls of hair follicle cycling.Physiol Rev. 2001; 81: 449-494Crossref PubMed Scopus (1033) Google Scholar)). Loss of cell adhesion between KCs may also be considered a catagen-promoting factor, as ICAM-1-deficient mice show significant catagen acceleration (Müller-Röver et al., 2000aMüller-Röver S. Bulfone-Paus S. Handjiski B. Welker P. Sundberg J.P. McKay I.A. et al.Intercellular adhesion molecule-1 and hair follicle regression.J Histochem Cytochem. 2000; 48: 557-568Crossref PubMed Scopus (22) Google Scholar). This loss of cell adhesion leads to a progressive reduction in the size of the proximal hair bulb (early and mid-catagen) and to rapid shortening of the outer and inner root sheaths and hair shaft (mid- and late catagen). Catagen is also characterized by the formation of a specialized structure in the HF, the club hair, that connects the proximal part of the hair shaft with surrounding HF epithelium and anchors hair in the telogen HF (Parakkal, 1970Parakkal P.F. Morphogenesis of the hair follicle during catagen.Z Zellforsch Mikrosk Anat. 1970; 107: 174-186Crossref PubMed Scopus (36) Google Scholar; Pinkus et al., 1981Pinkus H. Iwasaki T. Mishima Y. Outer root sheath keratinization in anagen and catagen of the mammalian hair follicle. A seventh distinct type of keratinization in the hair follicle: trichilemmal keratinization.J Anat. 1981; 133: 19-35PubMed Google Scholar). During catagen, the dermal papilla is transformed into a cluster of quiescent cells closely adjacent to the regressing HF epithelium, which moves from the subcutis to the dermis/subcutis border to contact the distal portion of the HF epithelium, including the secondary hair germ and bulge. In the hairless gene mutation, the disintegration of the dermal papilla and the HF epithelium during catagen leads to the loss of the capacity of the HF to reenter anagen (Ahmad et al., 1998Ahmad W. ul Haque M.F. Brancolini V. Tsou H.C. ul Haque S. Lam H.M. et al.Alopecia universalis associated with a mutation in the human hairless gene.Science. 1998; 279: 720-724Crossref PubMed Scopus (339) Google Scholar; Panteleyev et al., 1999Panteleyev A.A. Botchkareva N.V. Sundberg J.P. Christiano A.M. Paus R. The role of the hairless (hr) gene in the regulation of hair follicle catagen transformation.Am J Pathol. 1999; 155: 159-171Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar). The physiological involution of the HF may be triggered by a variety of stimuli, including signaling via death receptors, and by the withdrawal of growth factors that maintain cell proliferation and differentiation in the anagen HF. Accumulating evidence suggests that apoptosis in every distinct HF compartment is regulated differently (Figure 3). Recent data based on monitoring of the fate of melanocytes during catagen in Trp2-LacZ transgenic mice suggest that distinct subsets of melanocytes (located in the bulge, in the outer root sheath, and above the dermal papilla; Botchkarev et al., 2001Botchkarev V.A. Komarova E.A. Siebehaar F. Botchkareva N.V. Sharov A.A. Komarov P.G. et al.p53 involvement in the control of murine hair follicle regression.Am J Pathol. 2001; 158: 1913-1919Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar) show different sensitivities to apoptosis (Sharov et al., 2005Sharov A.A. Tobin D.J. Sharova T.Y. Atoyan R. Botchkarev V.A. Fate of the melanocytes during hair follicle involution (catagen): leads and lessons from the Trp-2-LacZ transgenic mice.J Invest Dermatol. 2005; 125: 1259-1267Crossref PubMed Scopus (31) Google Scholar). Specifically, apoptosis occurs only in differentiated melanocytes that are located above the dermal papilla and express the Fas receptor, whereas the other subpopulations, which express the c-Kit receptor and Bcl-2, most likely survive catagen (Sharov et al., 2005Sharov A.A. Tobin D.J. Sharova T.Y. Atoyan R. Botchkarev V.A. Fate of the melanocytes during hair follicle involution (catagen): leads and lessons from the Trp-2-LacZ transgenic mice.J Invest Dermatol. 2005; 125: 1259-1267Crossref PubMed Scopus (31) Google Scholar). Thus, Fas signaling may contribute to melanocyte apoptosis during catagen, similar to that seen after exposure of HFs to chemotherapy (Sharov et al., 2003Sharov A.A. Li G.Z. Palkina T.N. Sharova T.Y. Gilchrest B.A. Botchkarev V.A. et al.Fas and c-Kit are involved in the control of hair follicle melanocyte apoptosis and migration in chemotherapy-induced hair loss.J Invest Dermatol. 2003; 120: 27-35Crossref PubMed Scopus (46) Google Scholar). Stem cell factor/c-Kit and Bcl-2 are two important candidate molecules that may promote melanocyte survival during catagen. Constitutive stem cell factor/c-Kit ablation or administration of c-Kit-neutralizing antibody leads to apoptosis and the disappearance of melanoblasts in mouse embryos (Ito et al., 1999Ito M. Kawa Y. Ono H. Okura M. Baba T. Kubota Y. et al.Removal of stem cell factor or addition of monoclonal anti-c-KIT antibody induces apoptosis in murine melanocyte precursors.J Invest Dermatol. 1999; 5: 796-801Crossref Scopus (81) Google Scholar). Bcl-2 specifically protects the melanocyte stem cells in the HF from apoptosis, and Bcl-2 deficiency results in their apoptotic elimination and premature hair graying (Veis et al., 1993Veis D.J. Sorenson C.M. Shutter J.R. Korsmeyer S.J. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair.Cell. 1993; 75: 229-240Abstract Full Text PDF PubMed Scopus (1406) Google Scholar; Nishimura et al., 2005Nishimura E.K. Granter S.R. Fisher D.E. Mechanisms of hair graying: incomplete melanocyte stem cell maintenance in the niche.Science. 2005; 307: 720-724Crossref PubMed Scopus (538) Google Scholar). However, cross-talk between the stem cell factor/c-Kit pathway and mitochondrial antiapoptotic proteins in the control of melanocyte survival has yet to be further clarified. Data obtained from murine and human HFs suggest that apoptosis in hair matrix KCs is controlled by extrinsic and intrinsic pathways. The p55 subunit of the TNF receptor may be involved in the extrinsic apoptotic pathway, as it is expressed in the hair matrix during catagen, and TNF-α treatment results in an increase of TUNEL+ cells in the hair matrix (Lindner et al., 1997Lindner G. Botchkarev V.A. Botchkareva N.V. Ling G. van der Veen C. Paus R. et al.Analysis of apoptosis during hair follicle regression (catagen).Am J Pathol. 1997; 151: 1601-1617PubMed Google Scholar; Ruckert et al., 2000Ruckert R. Lindner G. Bulfone-Paus S. Paus R. High-dose proinflammatory cytokines induce apoptosis of hair bulb keratinocytes in vivo.Br J Dermatol. 2000; 143: 1036-1039Crossref PubMed Scopus (65) Google Scholar). Also, TNF-α promotes anagen-catagen transition in human HFs in vitro (Hoffmann et al., 1996Hoffmann R. Eicheler W. Huth A. Wenzel E. Happle R. Cytokines and growth factors influence hair growth in vitro. Possible implications for the pathogenesis and treatment of alopecia areata.Arch Dermatol Res. 1996; 288: 153-156Crossref PubMed Scopus (70) Google Scholar). Apoptosis in hair matrix KCs is also accompanied by the activation of intrinsic apoptotic pathways. During catagen in mice, the Bcl-2/Bax ratio in hair matrix KCs is markedly decreased, compared with anagen levels (Figure 2b and c) (Lindner et al., 1997Lindner G. Botchkarev V.A. Botchkareva N.V. Ling G. van der Veen C. Paus R. et al.Analysis of apoptosis during hair follicle regression (catagen).Am J Pathol. 1997; 151: 1601-1617PubMed Google Scholar). The Survivin protein, which belongs to the IAP family, is prominently expressed in the proliferating cells of the hair matrix, whereas its expression is progressively decreased during catagen (Botchkareva et al., 2005Botchkareva N.V. Ahluwalia G. Shander D. Involvement of survivin in hair growth control.J Invest Dermatol. 2005; 124: A103Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar). The p53 transcription factor also plays an important role in regulation of apoptosis in hair matrix KCs: catagen HFs of p53-null mice contain fewer apoptotic cells and show significantly retarded catagen progression, compared with catagen HFs of wild-type mice (Botchkareva et al., 2001Botchkareva N.V. Khlgatian M. Longley B.J. Botchkarev V.A. Gilchrest B.A. SCF/c-kit signaling is required for cyclic regeneration of hair pigmentation unit.FASEB J. 2001; 15: 645-658Crossref PubMed Scopus (187) Google Scholar). p53 may promote the intrinsic apoptotic pathway in hair matrix by regulating the expression of the mitochondrial protein Bax, as such expression is increased in the hair matrix during catagen (Lindner et al., 1997Lindner G. Botchkarev V.A. Botchkareva N.V. Ling G. van der Veen C. Paus R. et al.Analysis of apoptosis during hair follicle regression (catagen).Am J Pathol. 1997; 151: 1601-1617PubMed Google Scholar; Botchkareva et al., 2001Botchkareva N.V. Khlgatian M. Longley B.J. Botchkarev V.A. Gilchrest B.A. SCF/c-kit signaling is required for cyclic regeneration of hair pigmentation unit.FASEB J. 2001; 15: 645-658Crossref PubMed Scopus (187) Google Scholar). The hairless transcription factor also serves as an important regulator of apoptosis in the HF: in hairless mice, apoptosis in hair matrix KCs is strongly increased, leading to a premature switch from anagen to catagen and eventually resulting in disintegration of the dermal papilla from the follicular epithelium and permanent hair loss (Ahmad et al., 1998Ahmad W. ul Haque M.F. Brancolini V. Tsou H.C. ul Haque S. Lam H.M. et al.Alopecia universalis associated with a mutation in the human hairless gene.Science. 1998; 279: 720-724Crossref PubMed Scopus (339) Google Scholar; Panteleyev et al., 1999Panteleyev A.A. Botchkareva N.V. Sundberg J.P. Christiano A.M. Paus R. The role of the hairless (hr) gene in the regulation of hair follicle catagen transformation.Am J Pathol. 1999; 155: 159-171Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar; Panteleyev et al., 2000Panteleyev A.A. Paus R. Christiano A.M. Patterns of hairless (hr) gene expression in mouse hair follicle morphogenesis and cycling.Am J Pathol. 2000; 157: 1071-1079Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar). It was recently shown that hairless protein serves as a transcriptional co-repressor for the vitamin D receptor (Hsieh et al., 2003Hsieh J.C. Sisk J.M. Jurutka P.W. Haussler C.A. Slater S.A. Haussler M.R. et al.Physical and functional interaction between the vitamin D receptor and hairless corepresso
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