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J. Biol. Chem., Vol. 280, Issue 45, 37725-37731, November 11, 2005
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Glucocorticoid-induced Tumor Necrosis Factor Receptor Is a p21Cip1/WAF1 Transcriptional Target Conferring Resistance of Keratinocytes to UV Light-induced Apoptosis*
11
2
From the
Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, Telethon Institute of Genetics and Medicine, 80131 Naples, Italy, ¶Abramson Comprehensive Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, the ||Department of Clinical and Experimental Medicine, Pharmacology Section, Perugia University Medical School, Perugia, Italy, **Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, and the Department of Biochemistry, University of Lausanne, Epalinges 1066 CH, Switzerland
Received for publication, July 21, 2005 , and in revised form, August 15, 2005.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Glucocorticoid-induced tumor necrosis factor receptor (GITR) is a member of the tumor necrosis factor receptor superfamily, is expressed in T lymphocytes, and exerts an anti-apoptotic function in these cells. We reported that GITR is also highly expressed in the skin, specifically in keratinocytes, and that it is under negative transcriptional control of p21Cip1/WAF1, independently from the cell cycle. Although GITR expression is higher in p21-deficient keratinocytes and skin, it is down-modulated with differentiation and in response to UVB. The combined analysis of keratinocytes with increased GITR expression versus normal keratinocytes and skin of mice with a disruption of the GITR gene indicates that this protein protects keratinocytes from UVB-induced apoptosis both in vitro and in vivo.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The tumor necrosis factor receptor (TNFR)3 family of cell surface receptors and their cognate ligands play a key role in normal homeostasis of many tissues, their response to environmental cues, and in specific cases, during development (1). These receptors are type I transmembrane proteins sharing significant homology in their extracellular ligand-binding domains and are activated by a common mechanism involving ligand-induced trimerization. The cytoplasmic region of these molecules is characterized by the presence of one or both of two important classes of protein-binding motifs, which are required for downstream signaling. The TRAF-binding motif mediates recruitment of different TRAFs to the membrane receptor complex, with downstream activation of NF-
B signaling and associated protection against apoptosis (2). Conversely, "death domains" play a crucial role in the transmission of cell death signals through activation of the caspase cascade (3). Two functionally distinct classes of TNFR family members exist, depending on whether they contain the TRAF-binding motif alone or in conjunction with the death domain (1, 4).
Glucocorticoid-induced tumor necrosis factor receptor (also called TNFRSF18) was originally identified as a glucocorticoid dexamethasone-responsive gene in a murine hybridoma T cell line (5). This molecule shares high homology in the intracellular domain with 4-1BB and CD27, two other T cell-specific members of the TNFR family, which function as accessory molecules in lymphocyte activation, proliferation, and differentiation (6). All three of these receptors lack death domains. GITR has been implicated in the protection of T cells against T cell receptor-induced apoptosis and is also involved in the regulation of T cell activation (5, 6). The natural ligand of GITR was identified and shown to abrogate regulatory T cell suppression (7, 8).
p21WAF1/Cip1 is a well known cyclin/CDK-dependent inhibitor (CKI) and a direct transcriptional target of p53. This molecule has also been variously implicated as either a negative or positive regulator of apoptosis, with cell type-specific mechanisms that may depend on its effects on the cell cycle or more direct association and modulation of pro-apoptotic molecules (9–13). Additionally, p21WAF1 has been implicated in the control of transcription, through a mechanism that may be coupled to its CKI activity but also direct association and modulation of transcription factors and/or transcription coactivators (14–20). Keratinocytes provide an example where the complex function of p21WAF1 in growth/differentiation control has been well studied. Although this CKI contributes to cell cycle withdrawal associated with the early steps of differentiation, it is also part of a negative regulatory mechanism that needs to be inactivated for the later events to occur (21). Keratinocytes are also the main direct target of sunlight and UVB exposure, and p21WAF1 plays an important but complex role in the UVB response and apoptosis both in vitro and in vivo (22–26). As part of our further studies on p21, we have found that GITR is a transcriptional target of this CKI, that it is highly expressed in the skin, specifically in keratinocytes, and that it exerts a protective function against UVB-induced apoptosis, both in culture and in the intact skin.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Cell Culture and Viral Infection
Primary mouse keratinocytes were prepared and cultured in minimal essential medium with 4% Chelex-treated fetal calf serum (Hyclone), epidermal growth factor (10 ng/ml; BD Biosciences), and 0.05 mM CaCl2 (low calcium medium) as described previously (27). Keratinocyte differentiation was induced by addition of 2 mM CaCl2. Retroviral infections were carried out as described previously (27).
UVB Treatment
In Vitro—Freshly confluent keratinocyte cultures (around 5 x 105 cells per 60-mm dish) were used for in vitro UVB treatment. After removal of culture medium and two PBS washes, cells were covered with PBS (1.5 ml per 60-mm dish) and exposed to 25, 50, and 100 mJ/cm2 UVB using a custom-made UVB irradiation apparatus with four photochemical lamps (RPR 3000, Southern N.E. Ultraviolet Co., Bradford, CT). The distance between cells and UVB lamps was 4.5 cm. The delivered UVB dose was measured each time by using a photometer (model IL 1400A, International Light, Inc., Newburyport, MA). After UVB exposure, PBS was removed from cells and replaced with culture medium. Cells were harvested at 6 or 24 h after UVB treatment for RNA isolation and total protein extract preparation.
In Vivo— 8–9-Week-old female mice were used for in vivo UVB treatment studies. Mice were shaved 2 days prior to UVB treatment. They were exposed to a UVB dose of 160 mJ/cm2 at a distance of 22 cm from the lamp. Dorsal skins were harvested 24 or 48 h later and processed either for immunohistochemical analysis or for epidermis separation and total RNA preparation as described previously (17).
Analysis of Gene Expression
Gene expression was compared by quantifying mRNA levels by real time RT-PCR. For this, total RNA preparations (1–2 µg) were used in a reverse transcriptase reaction with oligonucleotide dT primers, followed by real time PCR with gene-specific primers (GITR: forward primer, 5'-GAC GGT CAC TGC AGA CTT TG-3'; reverse primer, 5'-GCC ATG ACC AGG AAG ATG AC-3'), using an Icycler IQTM real time detection system (Bio-Rad) according to the manufacturer's recommendation, with SYBR Green (Applied Biosystems) for detection. Each sample was tested in triplicate, and the results were normalized by real time PCR of the same cDNA with GAPDH primers (GAPDH: forward primer, 5'-GTG TTC CTA CCC CCA ATG TG-3'; reverse primer, 5'-GGA GAC AAC CTG GTC CTC AG-3').
Antibodies, Immunoblot, and Immunofluorescence Analysis
Goat polyclonal antibodies against mouse GITR/TNFRSF18 were obtained from R & D Systems. Rabbit polyclonal antibodies against caspase 3 and cleaved caspase-3 (Asp-175) were obtained from Cell Signaling. Immunoblots were performed as described previously (27).
For immunofluorescence analysis, frozen sections of newborn mouse skin were fixed in cold acetone for 10 min and blocked with 10% normal mouse serum for 30 min at room temperature. Sections were subsequently incubated with goat polyclonal antibodies against mouse GITR and rhodamine-conjugated anti-goat secondaries. Sections were counterstained with DNA dye Hoechst 33258.
TUNEL Assays—Keratinocytes were fixed with 4% paraformaldehyde for 30 min at room temperature, followed by treatment with 0.25% Triton X-100 in 0.1% sodium citrate for 5 min, and staining with TUNEL reaction mixture (In Situ Cell Death Detection kit, TMR Red, Roche Applied Science). TUNEL-positive cells were counted by taking three pictures from each group and examining more than 300–500 cells for each image. For in vivo analysis, TUNEL assays were carried out on de-paraffinized and re-hydrated sections of 10% formalin-fixed skin using the In Situ Cell Death Detection kit (Roche Applied Science). The fraction of TUNEL-positive cells was determined by taking pictures of three independent fields from each section and counting, for each image, the numbers of apoptotic cells per 100–120 nuclei of basal layer epidermal cells. The standard deviation among values obtained for each independent image was calculated and expressed as error bars. p values were calculated by independent Student's t test.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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GITR, a TNFR Family Member Expressed in Keratinocytes, Is a Transcriptional Target of p21Cip1/WAF1—The CDK inhibitor p21Cip1/WAF1 has been implicated in control of gene expression in both cell cycle-dependent and -independent methods (28). To probe into the complex function of p21 in keratinocytes, we undertook a comprehensive global analysis of gene expression in cells with increased p21 expression or lacking the p21 gene. This analysis pointed to GITR (also called TNFRSF18), reported previously to be expressed in T cells (29), as a possible transcriptional target that is negatively regulated by p21 in keratinocytes.
Real time RT-PCR analysis of RNA derived from various tissues showed that GITR is specifically expressed in skin and, to a much lower extent, in lung and intestine (Fig. 1A). Immunohistochemistry with antibodies against mouse GITR revealed a localized pattern of expression of this protein in the developing epidermis in vivo, at hair follicle budding sites (Fig. 1B), with expression becoming more diffuse by birth (Fig. 1C). Later on expression was restricted to the basal compartments of the skin, with weaker expression in the basal layer of the epidermis, and stronger expression in the outer root sheath and matrix of the hair follicle.
GITR was found to be expressed also in cultured mouse primary keratinocytes and to be substantially down-modulated as a consequence of increased expression of the p21WAF1/Cip1 protein, as achieved by recombinant adenovirus infection (Fig. 2A). Suppression of GITR expression by p21 was unlinked from effects on the cell cycle, as no down-modulation of this gene was caused by expression of the p21 N-terminal domain or of the related cyclin/CDK inhibitor p27, both of which cause cyclin/CDK inhibition and growth arrest in keratinocytes to an extent similar to full-length p21 (21). Most intriguingly, expression of the p21 C-terminal domain, which exerts relatively weak growth inhibition in keratinocytes,4 caused a similar suppression of GITR expression as the full-length protein (Fig. 2A).
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-actin. 293T cells infected with GITR transducing (retro-GITR) retroviruses served as a positive control. D, localization of endogenous GITR protein expression in skin of p21+/+ versus p21-/- mice. Same image capture conditions were used in all cases, and the more intense signal intensity in the p21-/- skin was observed throughout the sections.To assess whether GITR expression is under the control of endogenous p21 and whether the GITR gene is controlled with differentiation, we analyzed primary keratinocytes derived from p21+/+ versus p21-/- mice, under growing versus differentiating conditions. As shown in Fig. 2B, GITR mRNA levels were found to be substantially higher in p21-/- keratinocytes than in their wild type counterparts, consistent with endogenous p21 functioning as a negative regulator of GITR expression. Expression of the GITR gene was suppressed with differentiation as induced by increased concentrations of extracellular calcium. Although such down-modulation occurred also in p21-/- cells, GITR mRNA levels in these cells remained significantly higher than in the wild type, even after induction of differentiation (Fig. 2B). Similar differences in GITR expression were also observed at the protein level, by immunoblot analysis of extracts of wild type versus p21-/- keratinocytes, except that, upon induction of differentiation, no GITR protein was detected even in the p21-/- cells (Fig. 2C).
Consistent with the in vitro results, immunofluorescence analysis revealed that the GITR protein is mostly localized to the basal layer of the intact skin, with a greater signal intensity being obtained with the skin of p21-/- mice (Fig. 2D). Differences in GITR expression in vivo were confirmed and quantified by real time RT-PCR analysis of RNA derived from the epidermis of p21+/+ versus p21-/- mice (as shown further below).
GITR Exerts a Protective Function in Keratinocytes against UVB-induced Apoptosis—UVB triggers a complex response in keratinocytes, including activation of the p53–p21 pathway (22). We first investigated whether GITR is regulated by UVB treatment in keratinocytes. Real time RT-PCR and immunoblot analysis showed that GITR mRNA and protein are both down-regulated by UVB in mouse primary keratinocytes in a dose-dependent manner (Fig. 3, A and B). UVB treatment of p21-/- keratinocytes also caused a reduction of GITR expression, which remained at substantially higher levels than in the controls (Fig. 3, A and B). To assess the validity of the above results in vivo, p21+/+ and p21-/- mice of the same genetic background were exposed to UVB and sacrificed 24–48 h later. Real time RT-PCR analysis of RNA derived from the isolated epidermis indicated that even in vivo GITR expression is significantly decreased in response to UV light treatment of wild type mice (Fig. 3C); such down-modulation also occurred in p21-/- animals, but GITR levels remained higher than in controls (Fig. 3C).
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To assess whether endogenous GITR plays a role in UVB-induced apoptosis, we made use of mice with a homozygous disruption of the GITR gene (30). These mice have normal skin development. When primary keratinocytes derived from the GITR-/- mice and genetically matched wild type controls were exposed to UVB, we found that lack of GITR resulted in a substantially higher fraction of apoptotic cells (Fig. 4A). In parallel with these findings, levels of activated caspase 3 after UV light treatment were higher in the GITR knock out than wild type keratinocytes (Fig. 4B). To determine whether GITR exerts a similar anti-apoptotic function in vivo, GITR-/- mice and genetically matched wild type controls in the resting phase of the hair cycle (8 weeks old) were exposed to UVB, and the fraction of TUNEL-positive cells in their epidermis was determined at 48 h after UVB exposure. As shown in Fig. 4C, a significantly higher number of apoptotic keratinocytes was found in the GITR-/- mice, whereas the hyperplastic response triggered by UVB exposure appeared similar to that of the controls (not shown).
Similar UVB treatment experiments were repeated with primary keratinocytes with or without deletion of the p21 gene and with p21-/- mice versus wild type controls. The lack of the p21 gene was found to produce effects opposite those lacking GITR in that it conferred a partial resistance to UVB-induced apoptosis to both keratinocytes in culture and in the intact skin (Fig. 5, A and B). Such effects could be due, at least in part, to the increased GITR expression associated with loss of p21 function. To assess directly whether GITR can by itself exert a protective function against UV light-induced apoptosis, we evaluated the consequences of persistent GITR expression in UV light-treated keratinocytes where, as shown above, endogenous GITR expression is suppressed. Accordingly, cells were infected with a GITR-expressing retrovirus versus empty vector control (5). As shown in Fig. 6A, UVB exposure resulted in a significant reduction of apoptosis, as evaluated by TUNEL assays, in the GITR overexpressing keratinocytes. Such protective effects were accompanied by decreased levels of caspase 3 activation in response to UV light treatment, as assessed by immunoblotting with the corresponding antibodies (Fig. 6B).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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p21 is a major effector of cell cycle arrest downstream of p53 activation. This molecule has also been variously implicated in positive or negative control of apoptosis, in a manner that may still depend on its effects on the cell cycle and/or be due to direct binding and regulation of pro-apoptotic molecules or more indirect effects at the level of gene transcription (9–13). Concerning this latter aspect, p21 can bind to specific transcription factors such as c-Myc, E2F, STAT3, C/EBP-
, and estrogen receptor as well as transcriptional coactivators, such as p300, modulating their function (20, 28). Recently, p21 was found to associate specifically with the promoter region of individual genes, controlling their expression (17, 20). In keratinocytes, underlying its role in control of stem cell populations and tumor suppression, p21 negatively regulates transcription of the Wnt4 gene, by binding to the TATA box proximal region of the Wnt4 promoter in association with E2F1. We have shown here that GITR, a TNFR family member previously implicated in T cell pro-survival function (5), is another transcriptional target of p21 in keratinocytes whose expression, like that of Wnt4, is down-modulated by increased p21 levels independently of the cell cycle. The promoter region of the mouse GITR gene contains also multiple E2F1-binding sites (at position -1481, -1833, and -2643 relative to the ATG), suggesting that expression of this gene may be controlled by p21 through a direct binding mechanism similar to that for Wnt4 (17). Alternatively, GITR down-modulation may be a more indirect result of the complex cell cycle-independent functions that p21 can play in cells (9–13).
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Several TNFR family members have been studied for their expression and function in the skin. During embryonic development, a specific TNFR family member, EDAR, plays an important role in the morphogenetic events that lead to hair follicle formation (31). Most interestingly, we have found that GITR exhibits a highly localized pattern of expression in the skin similar to EDAR during development. However, GITR-/- mice show no defects in hair follicle formation and no accentuation of the EDAR-/- phenotype was observed in mice with double mutations of the two genes.4 Although the pattern of GITR expression in the epidermis becomes more widespread with birth, it remains limited to the basal proliferating layer, with increased but still basal expression in the p21-/- skin. Consistent with the in vivo findings, even in culture GITR is more highly expressed in p21-/- than p21+/+ keratinocytes, and in both cases it is strongly down-modulated with differentiation. The functional significance of this decreased expression remains to be clarified, as persistent GITR expression had no evident effects on differentiation (data not shown).
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GITR expression was also found to be down-modulated in keratinocytes upon UVB exposure, both in vivo and in vitro. In p21-/- keratinocytes and skin, GITR expression was also reduced in response to UVB. However, the total levels of this protein remained higher than in the controls, possibly contributing to the relative resistance of p21-/- keratinocytes to UVB-induced apoptosis both in vitro and in vivo. Two other TNFR family members, TNFR1 and Fas, have been implicated previously in the keratinocyte UVB response. Activation of these receptors by increased ligand expression can play an important role in UV light-induced apoptosis of these cells (32). However, UV light exposure can also directly cause cross-linking and activation of Fas receptors, independent of ligand binding, with the consequent engagement of the downstream death signaling machinery (33). GITR and closely related family members, 4-1BB, CD27, and OX40, are characterized by a relatively short cytoplasmic domain (39–52 amino acids) that can bind TRAF molecules with consequent activation of NF-
B and cell survival pathways (6). However, GITR family members can also bind Siva, a pro-apoptotic molecule, with consequent activation of the cell death program (6). In T cells, where GITR function has been studied so far, activation of this receptor can activate either TRAF- or Siva-dependent pathways, according to biological context and/or the intensity of T cell receptor and GITR ligand stimulation (34, 35). In keratinocytes and skin, where the GITR ligand is also expressed,4 our findings are indicative of a GITR protective role against UVB-induced apoptosis. An attractive possibility for future studies is that enhancement of GITR function in the skin via pharmacological manipulation may cause protection against the UVB detrimental effects. |
FOOTNOTES |
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* This work was supported by National Institutes of Health Grants AR39190, CA16038, and CA73796 and a grant from the Swiss National Foundation (to G. P. D.). 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.
1 Both authors contributed equally to this work.
2 To whom correspondence should be addressed: Dept. of Biochemistry, University of Lausanne, Chemin de Boveresses 155, CH-1066 Epalinges, Switzerland. Tel.: 41-21-692-5720; Fax: 41-216925705; E-mail: gdotto{at}partners.org.
3 The abbreviations used are: TNFR, tumor necrosis factor receptor; GITR, glucocorticoid-induced tumor necrosis factor receptor; TRAFs, TNFR-associated factors; RT, reverse transcription; TUNEL, terminal dUTP nick-end labeling; GFP, green fluorescent protein; PBS, phosphate-buffered saline; CDK, cyclin-dependent kinase; CKI, CDK-dependent inhibitor; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; UVB, ultraviolet B light.
4 C. Missero and G. P. Dotto, unpublished observations.
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