This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sharov, A. A. Articles by Botchkarev, V. A. Search for Related Content PubMed PubMed Citation Articles by Sharov, A. A. Articles by Botchkarev, V. A.

Fas Signaling Is Involved in the Control of Hair Follicle Response to Chemotherapy

¹ Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts; and ² Department of Dermatology, Johannes Gutenberg-University, Mainz, Germany

	ABSTRACT

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS AND DISCUSSION REFERENCES

 
Chemotherapeutic agents induce p53-dependent apoptosis in the hair follicle (HF) resulting in hair loss, a common side effect of cancer therapy. Here, we show that Fas as a p53 target plays important role in the HF response to cyclophosphamide. Specifically, we demonstrate that Fas is up-regulated in HF keratinocytes after cyclophosphamide treatment, Fas ligand–neutralizing antibody partially inhibits HF response to cyclophosphamide in wild-type mice, and Fas knockout mice show significant retardation of cyclophosphamide-induced HF involution associated with reduced Fas-associated death domain and caspase-8 expression. These data raise a possibility to explore blockade of Fas signaling as a part of complex local therapy for inhibiting keratinocyte apoptosis and hair loss induced by chemotherapy.

	INTRODUCTION

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS AND DISCUSSION REFERENCES

 
Hair loss (alopecia) is a common side effect of many chemotherapeutic protocols and is one of the most distressing aspects of cancer therapy. Because of the rapid proliferation of hair matrix keratinocytes during hair shaft production, the hair follicle (HF) represents a "by-stander" target for many chemotherapeutic agents (1 , 2) . It was recently shown that at least the p53 and cyclin-dependent kinase 2 molecular signaling pathways are involved in mediating HF response to chemotherapy (3 , 4) . In particular, we showed that p53 is essential for triggering apoptotic cell death in the HF induced by cyclophosphamide (CYP) and that genetic loss of p53 results in a complete resistance of murine HF to chemotherapy (3) .

p53 promotes apoptotic cell death induced by chemotherapy through transcription- dependent and -independent mechanisms (reviewed in refs. 5, 6, 7 ). Many transcriptional effects of p53 in regulating the apoptotic program are mediated by Fas (APO-1, CD95), a gene product that induces apoptosis in multiple cell types under physiological and pathological conditions (8) . The Fas gene is a direct p53 target and becomes activated when the p53 consensus element in its promoter interact with p53 (9 , 10) . Fas ligand expression is also transcriptionally regulated by p53 (11) , and keratinocytes from Fas ligand–deficient mice exposed to UV radiation show a significant decrease of apoptosis associated with markedly increased frequency of p53 mutations, compared with keratinocytes from wild-type mice (12) . Apoptotic signaling through the Fas receptor requires its interaction with the intracellular adaptor molecule Fas-associated death domain (FADD), which in turn promotes activation of procaspase-8 and its recruitment into the death-inducing signaling complex (reviewed in refs. 8 and 13 ). Procaspase-8 after proteolytic activation induces activation of caspase-3 along the common final pathway of apoptosis (13) .

Fas is expressed in HF keratinocytes of C57BL/6 mice after CYP treatment but is strongly reduced in the HF of p53 knockout mice (3 , 14) . However, the role of Fas in the control of chemotherapy-induced apoptosis in HF keratinocytes remains to be elucidated. Here, using a mouse model for chemotherapy-induced hair loss (15) , we show that CYP-induced HF involution is significantly retarded in Fas-deficient mice, compared with wild-type controls. Furthermore, we demonstrate that Fas ligand–neutralizing antibody partially inhibits HF response to CYP in wild-type mice. These data suggest the important role for Fas signaling as a downstream effector of p53 in mediating keratinocyte apoptosis and HF involution induced by chemotherapy.

	MATERIALS AND METHODS

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS AND DISCUSSION REFERENCES

 
Animal Models and Tissue Collection.
Eight-week-old C57BL/6 female mice (n = 20), 8- to 10-week-old Fas knockout mice (n = 25), and wild-type mice (n = 25) were purchased from Charles River (Boston, MA) and The Jackson Laboratory (Bar-Harbor, ME). Fas knockout mice generated on C57BL/6 background were viable and showed apparently normal fur (16) . Mice were housed in community cages at the animal facilities of the Boston University School of Medicine. All mice were fed water and murine chow ad libitum and were kept under 12-hour light/dark cycles.

Active hair growth (anagen) was induced in the back skin by application of the wax-rosin mixture with subsequent depilation as described before (15 , 17) . On day 9 after hair cycle induction (at anagen VI stage of the hair cycle), a single i.p. injection of 150 mg/kg CYP (Endoxan; Bristol Meyers Squibb, Princeton, NJ) or PBS (vehicle control) was performed as described previously (15) . Skin samples were harvested at days 1, 3, 5, 7, 9, and 11 after CYP administration (at days 10, 12, 14, 16, 18, and 20 post depilation, respectively). Fas ligand–neutralizing antibody K10 (PharMingen, San Diego, CA) was used to block Fas ligand–mediated apoptosis in the hair follicle of wild-type mice via intracutaneous injection twice a day on days 9 to 15 after depilation. Skin was harvested on days 5 to 7 after CYP administration (days 14–16 after depilation). Skin harvesting and cryosectioning were performed using a special technique to obtain longitudinal sections of the hair follicles as described previously (15 , 17) .

Semiquantitative Reverse Transcription-Polymerase Chain Reaction.
Total RNA was isolated from full-thickness back skin of wild-type mice on days 1 and 2 after treatment by CYP or by vehicle control (at days 10 and 11 after depilation) using RNA-zolB RNA extraction (Invitrogen, Carlsbad, CA). The first-strand cDNA was synthesized with a first-strand cDNA synthesis kit (Invitrogen, Carlsbad, CA). Primers for Fas and Fas ligand were obtained from R&D Systems (Minneapolis, MN). For analyses of ß-actin transcripts, the following primers were used: 5-TGGAATCCTGTGGCATCCATGAAAC-3' and 5'-TAAAACGCAGCTCAGTAACAGTCCG-3'. Amplification was performed using Taq polymerase over 35 cycles, using an automated thermal cycler (Perkin-Elmer, Boston, MA). Each cycle consisted of the denaturing at 92°C (1 min), annealing at 55°C to 58°C (45 seconds), and extension at 72°C (45 seconds). PCR products were analyzed by agarose gel electrophoresis. Staining was densitometrically assessed with a video scanner using Scan Pack 2.0 (Biometra, Tampa, FL) as described previously (18) .

Immunohistochemistry, Terminal Deoxynucleotidyltransferase-Mediated Nick End Labeling, and Confocal Microscopy.
Expressions of Fas, phospho-FADD, and caspase-8 were assessed using corresponding primary antisera (PharMingen, San Diego, CA; Cell Signaling, Beverly, MA; Neomarkers, Fremont, CA) and tyramide amplification method as described previously (3 , 19) . Double immunovisualization of Fas and terminal deoxynucleotidyltransferase-mediated nick end labeling (TUNEL) was performed as described previously (20 , 21) . In all immunofluorescence procedures, nuclei were counterstained by TO-PRO-3. Multicolor confocal microscope (Zeiss, Jena, Germany) and digital image analysis system were used for analysis and preparation of images.

Histomorphometry.
Immunoreactivity patterns were scrutinized by studying at least 50 different HF per mouse, and five mice were assessed per hair cycle stage. For the precise identification of the defined stages of HF cycling, histochemical detection of endogenous alkaline phosphatase activity was used as described, because this allows visualizing the morphology of dermal papilla as a useful morphological marker for staging HF cycling (22) . The percentage of HFs at distinct catagen stages was assessed and calculated in Fas knockout (–/–) and corresponding age-matched wild-type mice. All evaluations were performed on the basis of accepted morphological criteria of HF classification (22) . Only every tenth cryosection was used for analysis to exclude the repetitive evaluation of the same HF, and two to three cryosections were assessed from each animal. All together, 250 to 300 HFs in 50 to 60 microscopic fields, derived from six animals (approximately 40–50 follicles per animal) of distinct age were analyzed and compared with those with a corresponding number of HFs from the appropriate, age-matched wild-type mice. Number of TUNEL-positive cells was assessed in the hair matrix of catagen II to III HFs in Fas knockout and wild-type animals. In total, 40 to 50 such measurements were performed in 50 to 60 microscopic fields derived from three animals per mutant and wild-type group. All sections were analyzed at x200 to x400 magnification, and means and SE were calculated from pooled data. Differences were judged as significant if the P value was less than 0.05, as determined by the independent Student’s t test for unpaired samples.

	RESULTS AND DISCUSSION

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS AND DISCUSSION REFERENCES

 
Fas and Fas Ligand Are Increased and Colocalized with Terminal Deoxynucleotidyltransferase-Mediated Nick End Labeling in the Hair Follicles after Cyclophosphamide Treatment.
To examine the involvement of Fas signaling in chemotherapy-induced hair loss, we first compared the expression of Fas and Fas ligand in actively growing HFs in the C57BL/6 mouse back skin and in HFs treated by CYP. Hair growth phase (anagen) was induced by depilation as described before (22) , and CYP was administered 9 days post depilation, i.e., at the time point when all hair follicles reached stage of active hair shaft production (anagen VI; refs. 15 and 17 ).

Mice treated by vehicle control 10 days post depilation showed a relatively weak expression of Fas and Fas ligand in the precortex of the HF and absence of TUNEL- positive cells (Fig. 1A and B) . However, CYP-treated mice displayed a strong expression of Fas and Fas ligand in the HF matrix (Fig. 1C--F) . Twenty-four hours after CYP treatment, some TUNEL-positive apoptotic cells located in the hair matrix were also Fas positive and Fas ligand positive (Fig. 1C and D) . As it was shown previously (14 , 15 , 17) , 48 hours after CYP administration (day 11 post depilation), HFs showed a shortening of their length and decrease in volume of the hair bulb due to the massive apoptosis in the hair matrix. This was associated with prominent Fas and Fas ligand expression and colocalization of Fas and TUNEL in the regressing proximal part of the HF (Fig. 1E and F) . By reverse transcription-PCR, increased levels of Fas and Fas ligand transcripts were also seen in full-thickness mouse skin 24 hours after CYP administration, compared with skin treated by vehicle control (Fig. 1H) .

View larger version (52K): [in this window] [in a new window]   Fig. 1. Increase of Fas and Fas ligand expression and colocalization with TUNEL in the hair follicles of C57BL/6 mice after cyclophosphamide treatment. Hair cycle was induced in the back skin of C57BL/6 mice by depilation, and CYP was administered after 9 days. Skin was harvested at the indicated time points after CYP administration, and cryosections (8 µm thickness) were processed for double immunovisualization of Fas or Fas ligand and TUNEL (A–F). DP, dermal papilla; HM, hair matrix; IRS, inner root sheath; ORS, outer root sheath; EP, epidermis. H. Skin samples were also processed for reverse transcription-PCR for Fas, Fas ligand, and ß-actin. A–D, 24 hours after CYP treatment (day 10 post depilation). A and B, vehicle control. Expression of Fas and Fas ligand in the precortex of anagen HFs (red fluorescence, arrows). C and D, CYP treatment. Increase of Fas (C) and Fas ligand expression (D) in the hair matrix (red fluorescence, large arrows) and their colocalization with TUNEL (yellow fluorescence, small arrows). TUNEL+ cells that lacked of Fas or Fas ligand expression (green fluorescence) are shown by arrowheads. E and F, 48 hours after CYP treatment (day 11 post depilation). Strong expression of Fas (E) and Fas ligand (F) in the matrix of CYP-treated HFs (red fluorescence, large arrows) and colocalization with TUNEL (yellow fluorescence, small arrows). TUNEL+ cells not expressing Fas or Fas ligand show green fluorescence (arrowheads). G, 7 days after CYP treatment (day 16 after depilation). Absence of Fas and TUNEL in the HFs (arrows). Cell nuclei in A-G were counterstained by TO-PRO3. H, semiquantitative reverse transcription-PCR of total RNA isolated from full thickness skin of mice 24 hours after treatment by vehicle control or CYP with primers specific for Fas, Fas ligand, or ß-actin. Bars = 100 µm.

Anti-Fas Ligand–Neutralizing Antibody Inhibits Cyclophosphamide-Induced Apoptosis in the Hair Follicle In vivo.
To test the hypothesis that Fas signaling is involved in CYP-induced apoptosis in the HF, anti-Fas ligand–neutralizing antibody or 1% mouse normal serum (as vehicle control) was injected intracutaneously to C57BL/6 mice on days 9 to 15 after depilation (days 1–7 after CYP administration), and the dynamics of the CYP-induced HF involution was studied as described previously (15 , 17) . Seven days after CYP treatment (16 days post depilation), both control mice and mice treated by anti-Fas ligand–neutralizing Ab showed alopecia over the entire back (not shown). However, mice treated with anti-Fas ligand Ab clearly showed significant retardation of CYP-induced HF regression histologically, compared with the animals treated by vehicle control (Fig. 2A–C) . Seven days after CYP administration, most of the HFs in the control mice were already at the advanced stages of catagen (catagen V-VII), whereas the vast majority of HFs in mice treated by anti-Fas ligand Ab were at the beginning of catagen (catagen I–III; Fig. 2A–C ).

View larger version (58K): [in this window] [in a new window]   Fig. 2. Retardation of cyclophosphamide-induced hair follicle regression and reduction of apoptosis after administration of anti-Fas ligand–neutralizing antibody. The hair cycle was induced in the back skin of C57BL/6 mice (n = 9), and CYP was injected i.p. 9 days after depilation. Anti-Fas ligand–neutralizing antibody was administered intracutaneously on days 9 to 15 post depilation. Skin was harvested at day 7 after CYP administration (day 16 post depilation), and cryosections were processed for the histo-enzymatic detection of alkaline phosphatase to visualize the dermal papillae (A–C) or for immunovisualization of apoptosis by TUNEL (D–F). Cell nuclei in C, D were visualized by TO-PRO-3. A, vehicle control. Late catagen HFs in CYP-treated skin show shortening of their length and reduction in the volume of proximal hair bulb (arrows) associated with dramatic decrease of skin thickness. B, anti-Fas ligand Ab. Large volume of the proximal hair bulb (arrows) and dermal papilla suggest retardation of catagen in CYP-treated mice after administration of anti-Fas ligand Ab. C, histogram showing significant retardation of CYP-induced catagen development in mice treated by anti-Fas ligand Ab compared with vehicle control. Student’s t test, *, P < 0.05; **, P < 0.01. D, vehicle control. Numerous TUNEL+ cells are seen in the matrix (arrows) and the outer root sheath (arrowheads) of the HFs (dotted lines) 5 days after CYP treatment. E, anti-Fas ligand Ab. Single TUNEL+ cells in outer root sheath (arrowheads) are seen in CYP-treated HFs (dotted lines) after administration of anti-Fas ligand Ab. F, significant decrease in number of TUNEL+ cells in CYP-treated HFs after administration of anti-Fas ligand Ab compared with vehicle control. Student’s t test, *, P < 0.01.

Fas Knockout Mice Show Significantly Retarded Cyclophosphamide-Induced Hair Follicle Involution Associated with Reduced Expression of FADD and Caspase-8.
To further explore a role for Fas receptor signaling in the control of HF keratinocyte apoptosis induced by chemotherapy, we compared the effects of CYP on actively growing HFs between Fas knockout and wild-type mice. Animals of both strains were treated by CYP at day 9 post depilation as described above. Seven days after CYP treatment (16 days post depilation), wild-type mice showed severe alopecia over the entire back and were characterized by predominance of the HFs at advanced stages of catagen, as visualized by alkaline phosphatase staining (Fig. 3A) . Although Fas knockout mice also showed hair loss after CYP treatment (not shown), skin of Fas knockout mice seven days after treatment displayed a significant retardation of HF involution (P < 0.05), compared with wild-type mice. In contrast to wild-type skin, Fas-deficient skin showed a significantly higher percentage of HFs at early catagen stages (stages 1–2; P < 0.05) and significantly lower number of HFs at advanced stages of catagen (stages 5–7; P < 0.05; Fig. 3B and C ).

View larger version (116K): [in this window] [in a new window]   Fig. 3. Retardation of cyclophosphamide-induced hair follicle regression and decrease of FADD and caspase-8 expression in the hair follicles of Fas deficient mice. Hair cycle was induced in the back skin of wild-type and Fas-null mice by depilation, and CYP was administered 9 days after. Skin was harvested at day 7 after CYP treatment. Sections were stained for the detection of endogenous alkaline phosphatase activity to visualize the catagen stages (A–C) or processed for immunodetection of TUNEL (D and E), FADD (F and G) or caspase-8 (H and I). A and B. HFs in wild-type mice show shortening of the follicle length and reduction in hair bulb volume indicating for advanced catagen stages (A, arrows), whereas HFs in Fas knockout mice (B, arrows) show larger follicle length and larger volume of the hair bulb and dermal papilla, suggesting the early stages of catagen. Bars = 100 µm. C, significant retardation of CYP-induced catagen in Fas knockout mice compared with wild-type mice. Student’s t test, *, P < 0.05. D and E, TUNEL. Decrease of TUNEL+ cells in the HFs of Fas knockout mice (E, arrow) 24 hours after CYP treatment compared with wild-type mice (D, arrows). F and G, phospho-FADD. Decrease of expression in the matrix and outer and inner root sheath of the HFs of Fas knockout mice (G, large and small arrow, respectively) 24 hours after CYP treatment compared with the corresponding HF compartments of wild-type mice (G). H and I, caspase-8. Decrease of expression in the matrix and outer and inner root sheath of the HFs of Fas knockout mice (I, large arrow, small arrow, and arrowhead, respectively) 24 hours after CYP treatment compared with the corresponding HF compartments of wild-type mice (H).

Together, these data suggest that Fas signaling is an important pathway mediating apoptosis induced by CYP in the HF keratinocytes. Fas and Fas ligand show identical expression patterns in the HFs after CYP treatment (Fig. 1) strongly implicating autocrine mechanisms in Fas-mediated keratinocyte apoptosis. C57BL/6 mice treated by anti-Fas ligand antibody and Fas knockout mice show comparably and significantly retarded HF involution induced by CYP, associated with markedly reduced keratinocyte apoptosis (Figs. 2 and 3 ). Furthermore, inhibition of keratinocyte apoptosis seen in Fas knockout mice was accompanied by decreased expression of phospho-FADD and caspase-8, two important downstream components in the Fas-mediated apoptotic signaling pathway (Fig. 3) . These observations are consistent with previously published data that showed a role for Fas in the control of chemotherapy-induced apoptosis in many cell types including keratinocytes and HF melanocytes (9 , 10 , 12 , 19) .

These data also suggest a cross-talk between p53 and Fas signaling pathways during the HF response to chemotherapy, which is consistent with data obtained previously in other models (11) . However, the eventual hair loss seen in Fas knockout mice after CYP treatment demonstrates their lower resistance to chemotherapy, compared with p53 null mice (3) . Most likely, Fas signaling represents only a part of the apoptotic program activated by p53 in the HF keratinocytes during chemotherapy, and Fas deficiency does not affect apoptotic pathways controlled by other p53 targets (Bax, IGF-BP3, PTEN, etc.; reviewed in ref. 5 ) that may mediate chemotherapy-induced keratinocyte apoptosis in Fas knockout mice and hair loss.

Also, Fas deletion may not prevent alterations in the keratinocyte growth arrest and proliferation/differentiation transition induced by chemotherapy, which may also be mediated by p53. Indeed, p21^WAF1 as the transcriptional p53 target (23) that is expressed in post-mitotic keratinocytes of the growing HF (24) may mediate alterations in keratinocyte differentiation induced by chemotherapy in Fas knockout mice that result in hair loss. Thus, HF response to chemotherapy may be considered to be a complex process that includes massive apoptosis and altered differentiation of the HF keratinocytes, both of which are p53 dependent and partial inhibition of which may not prevent chemotherapy-induced hair shaft breakage and hair loss.

Taken together, these data suggest that Fas signaling serves as an important part of the apoptotic program mediated by p53 during HF response to chemotherapy. These data raise a possibility of exploring pharmacological blockade of Fas signaling as a part of complex local treatment for inhibiting keratinocyte apoptosis and reducing hair loss induced by chemotherapy of Fas-negative tumors.

	ACKNOWLEDGMENTS

 
The excellent technical assistance of L. Yelton is gratefully acknowledged.

	FOOTNOTES

 
Grant support: NIH grant CA092090 (V. Botchkarev).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: N. Botchkareva is currently at The Gillette Company, Needham, MA.

Requests for reprints: Vladimir A. Botchkarev, Department of Dermatology, Boston University School of Medicine, 609 Albany Street, Boston, MA 02118. Phone: 617-638-5548; Fax: 617-638-5515; E-mail: vladbotc{at}bu.edu

Received 4/16/04. Revised 6/16/04. Accepted 6/25/04.

	REFERENCES

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS AND DISCUSSION REFERENCES

 

1. Paus R, Cotsarelis G. The biology of hair follicles. N Engl J Med, 341: 491-7, 1999.[Free Full Text]
2. Botchkarev VA. Molecular mechanisms of chemotherapy-induced hair loss. J Investig Dermatol Symp Proc, 8: 72-5, 2003.[CrossRef][Medline]
3. Botchkarev VA, Komarova EV, Siebenhaar F, et al p53 is essential for chemotherapy-induced hair loss. Cancer Res, 60: 5002-6, 2000.[Abstract/Free Full Text]
4. Davis ST, Benson BG, Bramson HN, et al Prevention of chemotherapy-induced alopecia in rats by CDK inhibitors. Science, 291: 134-7, 2001.[Abstract/Free Full Text]
5. Fridman JS, Lowe SW. Control of apoptosis by p53. Oncogene, 22: 9030-40, 2003.[CrossRef][Medline]
6. Gudkov AV, Komarova EA. The role of p53 in determining sensitivity to radiotherapy. Nat Rev Cancer, 3: 117-29, 2003.[CrossRef][Medline]
7. Manfredi J. p53 and apoptosis: it’s not just in the nucleus anymore. Mol Cell, 11: 552-4, 2003.[CrossRef][Medline]
8. Curtin JF, Cotter TG. Live or let die: regulatory mechanisms in Fas-mediated apoptosis. Cell Signalling, 15: 983-92, 2003.[CrossRef][Medline]
9. Friesen C, Herr I, Krammer PH, Debatin KM. Involvement of the CD95 (APO- 1/FAS) receptor/ligand system in drug-induced apoptosis in leukemia cells. Nat Med, 2: 574-7, 1996.[CrossRef][Medline]
10. Muller M, Strand S, Hug H. Drug-induced apoptosis in hepatoma cells is mediated by the CD95 (APO-1/Fas) receptor/ligand system and involves activation of wild-type p53. J Clin Investig, 99: 403-13, 1997.[Medline]
11. Maecker HL, Koumenis CG, Giaccia AG. p53 promotes selection for Fas-mediated apoptotic resistance. Cancer Res, 60: 4638-44, 2000.[Abstract/Free Full Text]
12. Hill LL, Ouhtit A, Loughlin SM, Kripke ML, Ananthaswamy HN, Owen-Schaub LB. Fas ligand: a sensor for DNA damage critical in skin cancer etiology. Science, 285: 898-900, 1999.[Abstract/Free Full Text]
13. Peter ME, Krammer PH. The CD95(Apo-1/Fas) DISC and beyond. Cell Death Differ, 10: 26-35, 2003.[CrossRef][Medline]
14. Lindner G, Botchkarev VA, Botchkareva NV, Ling G, van der Veen C, Paus R. Analysis of apoptosis during hair follicle regression (catagen). Am J Pathol, 151: 1601-17, 1997.[Abstract]
15. Paus R, Handjiski B, Eichmuller S, Czarnetzki BM. Chemotherapy-induced alopecia in mice: induction by cyclophosphamide, inhibition by cyclosporine A, and modulation by dexamethasone. Am J Pathol, 144: 719-34, 1994.[Abstract]
16. Watanabe-Fukunaga R, Brannan CI, Copeland NG, Jenkins NA, Nagata S. Limphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature, 356: 314-7, 1993.
17. Paus R, Schilli MB, Handjiski B, Menrad A, Henz BM, Plonka P. Topical calcitriol enhances normal hair regrowth but does not prevent chemotherapy- induced alopecia in mice. Cancer Res, 56: 4438-43, 1996.[Abstract/Free Full Text]
18. Sharov AA, Weiner L, Sharova T, et al Noggin overexpression inhibits eyelid opening by altering epidermal apoptosis and differentiation. EMBO J, 22: 2992-3003, 2003.[CrossRef][Medline]
19. Sharov AA, Li GZ, Palkina TN, Sharova TY, Gilchrest BA, Botchkarev VA. Fas and c-kit are involved in the control of hair follicle melanocyte apoptosis and migration in chemotherapy-induced hair loss. J Investig Dermatol, 120: 27-35, 2003.[CrossRef][Medline]
20. Botchkarev VA, Botchkareva NV, Roth W, et al Noggin is a mesenchymally-derived stimulator of hair follicle induction. Nat Cell Biol, 1: 158-64, 1999.[CrossRef][Medline]
21. Botchkarev VA, Botchkareva NV, Albers KM, et al A role for p75 neurotrophin receptor in the control of apoptosis-driven hair follicle regression. FASEB J, 14: 1931-42, 2000.[Abstract/Free Full Text]
22. Muller-Rover S, Handjiski B, van der Veen C, et al A comprehensive guide for the accurate classification of murine hair follicles in distinct hair cycle stages. J Investig Dermatol, 117: 3-15, 2001.[CrossRef][Medline]
23. Zhao R, Gish K, Murphy M, et al Analysis of p53-regulated gene expression patterns using oligonucleotide arrays. Genes Dev, 14: 981-93, 2000.[Abstract/Free Full Text]
24. Mitsui S, Ohuchi A, Hotta M, Tsuboi R, Ogawa H. Genes for a range of growth factors and cyclin-dependent kinase inhibitors are expressed by isolated human hair follicles. Br J Dermatol, 137: 693-8, 1997.[CrossRef][Medline]

This article has been cited by other articles:

				E. Bodo, D. J. Tobin, Y. Kamenisch, T. Biro, M. Berneburg, W. Funk, and R. Paus Dissecting the Impact of Chemotherapy on the Human Hair Follicle: A Pragmatic in Vitro Assay for Studying the Pathogenesis and Potential Management of Hair Follicle Dystrophy Am. J. Pathol., October 1, 2007; 171(4): 1153 - 1167. [Abstract] [Full Text] [PDF]

				M. Y. Fessing, T. Y. Sharova, A. A. Sharov, R. Atoyan, and V. A. Botchkarev Involvement of the Edar Signaling in the Control of Hair Follicle Involution (Catagen) Am. J. Pathol., December 1, 2006; 169(6): 2075 - 2084. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sharov, A. A. Articles by Botchkarev, V. A. Search for Related Content PubMed PubMed Citation Articles by Sharov, A. A. Articles by Botchkarev, V. A.