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2.  Oral Curcuminoid C3 Complex® in the Treatment of Moderate to Severe Psoriasis Vulgaris: A Prospective Clinical Trial 
Background
There is a need for safe, inexpensive and effective psoriasis therapies. Many anecdotal accounts of patients’ successful treatment with the alternative medicine curcumin exist.
Objective
To determine the safety and efficacy of oral curcumin in psoriasis patients.
Methods
A phase II, open-label, Simon’s two-stage trial of 4.5g/d of oral Curcuminoid C3 Complex® in plaque psoriasis patients. Endpoints included improvement in Physicians Global Assessment, Psoriasis Area and Severity Index, and safety endpoints throughout the study.
Results
The intention to treat analysis response rate was 2/12 (95% CI: 2%, 48%) and both responders achieved a PASI 75. There were no study-related adverse events that necessitated subject withdrawal.
Limitations
Small sample size and lack of placebo group.
Conclusion
The response rate was low and possibly due to a placebo effect or the natural history of psoriasis. Large placebo-controlled studies are necessary prior to recommending oral curcumin as a psoriasis treatment.
doi:10.1016/j.jaad.2007.12.035
PMCID: PMC4131208  PMID: 18249471
3.  Reconstructing skin cancers using animal models 
Cancer metastasis reviews  2013;32(0):123-128.
The American Cancer Society estimates that skin cancer is the most prevalent of all cancers with over 2 million cases of nonmelanoma skin cancer each year and 75,000 melanoma cases in 2012. Representative animal cancer models are important for understanding the underlying molecular pathogenesis of these cancers and the development of novel targeted anticancer therapeutics. In this review we will discuss some of the important animal models that have been useful to identify important pathways involved in basal cell carcinoma, squamous cell carcinoma and melanoma.
doi:10.1007/s10555-012-9410-8
PMCID: PMC3625682  PMID: 23179861
4.  Targeted delivery of tumor necrosis factor-related apoptosis-inducing ligand to keratinocytes with a pemphigus monoclonal antibody 
We determined the feasibility of using an anti-desmoglein (Dsg) monoclonal antibody, Px44, to deliver a biologically active protein to keratinocytes. Recombinantly produced Px44-green fluorescent protein (GFP) injected into mice and skin organ culture delivered GFP to the cell surface of keratinocytes. We replaced GFP with tumor necrosis factor -related apoptosis-inducing ligand (TRAIL) to produce Px44TRAIL. We chose TRAIL as a biologic model because it inhibits activated lymphocytes and causes apoptosis of hyperproliferative keratinocytes, features of various skin diseases. Px44TRAIL formed a trimer, the biologically active form of TRAIL. Standard assays of TRAIL activity showed that Px44TRAIL caused apoptosis of Jurkat cells and inhibited interferon-γ production by activated CD4+ T cells. Enzyme-linked immunoassay with Px44TRAIL showed delivery of TRAIL to Dsg. Immunofluorescence with Px44TRAIL incubated on skin sections and cultured keratinocytes or injected into mouse skin, human organ culture or human xenografts detected TRAIL on keratinocytes. Px44TRAIL caused apoptosis of hyperproliferative, but not differentiating, cultured keratinocytes through binding to Dsg3. Foldon, a small trimerization domain, cloned into Px44TRAIL maintained its stability and biological activity at 37° for at least 48 hr. These data suggest that such targeted therapy is feasible and may be useful for hyperproliferative and inflamed skin diseases.
doi:10.1038/jid.2013.85
PMCID: PMC3681880  PMID: 23439393
5.  From keratinocyte to cancer: the pathogenesis and modeling of cutaneous squamous cell carcinoma 
Cutaneous squamous cell carcinoma (cSCC) is the second most common human cancer with over 250,000 new cases annually in the US and is second in incidence only to basal cell carcinoma. cSCC typically manifests as a spectrum of progressively advanced malignancies, ranging from a precursor actinic keratosis (AK) to squamous cell carcinoma (SCC) in situ (SCCIS), invasive cSCC, and finally metastatic SCC. In this Review we discuss clinical and molecular parameters used to define this range of cutaneous neoplasia and integrate these with the multiple experimental approaches used to study this disease. Insights gained from modeling cSCCs have suggested innovative therapeutic targets for treating these lesions.
doi:10.1172/JCI57415
PMCID: PMC3266779  PMID: 22293185
6.  Acute Biological Effects of Simulating the Whole-Body Radiation Dose Distribution from a Solar Particle Event Using a Porcine Model 
Radiation Research  2011;176(5):649-659.
In a solar particle event (SPE), an unshielded astronaut would receive proton radiation with an energy profile that produces a highly inhomogeneous dose distribution (skin receiving a greater dose than internal organs). The novel concept of using megavoltage electron-beam radiation to more accurately reproduce both the total dose and the dose distribution of SPE protons and make meaningful RBE comparisons between protons and conventional radiation has been described previously. Here, Yucatan minipigs were used to determine the effects of a superficial, SPE-like proton dose distribution using megavoltage electrons. In these experiments, dose-dependent increases in skin pigmentation, ulceration, keratinocyte necrosis and pigment incontinence were observed. Five of 18 animals (one each exposed to 7.5 Gy and 12.5 Gy radiation and three exposed to 25 Gy radiation) developed symptomatic, radiation-associated pneumonopathy approximately 90 days postirradiation. The three animals from the highest dose group showed evidence of mycoplasmal pneumonia along with radiation pneumonitis. Moreover, delayed-type hypersensitivity was found to be altered, suggesting that superficial irradiation of the skin with ionizing radiation might cause immune dysfunction or dysregulation. In conclusion, using total doses, patterns of dose distribution, and dose rates that are compatible with potential astronaut exposure to SPE radiation, animals experienced significant toxicities that were qualitatively different from toxicities previously reported in pigs for homogeneously delivered radiation at similar doses.
PMCID: PMC3382987  PMID: 21859326
7.  α-catenin is a tumor suppressor that controls cell accumulation by regulating the localization and activity of the transcriptional coactivator Yap1 
Science Signaling  2011;4(174):ra33.
The Hippo pathway regulates contact inhibition of cell proliferation and, ultimately, organ size in diverse multicellular organisms. Inactivation of the Hippo pathway promotes nuclear localization of the transcriptional coactivator Yap1, a Hippo pathway effector, and can cause cancer. Here, we show that deletion of αE-catenin in the hair follicle stem cell compartment resulted in the development of skin squamous cell carcinoma in mice. Tumor formation was accelerated by simultaneous deletion of αE-catenin and the tumor suppressor-encoding gene p53. An siRNA screen revealed a functional connection between αE-catenin and Yap1. By interacting with Yap1, αE-catenin promoted its cytoplasmic localization, and Yap1 showed constitutive nuclear localization in αE-catenin-null cells. We also found an inverse correlation between αE-catenin abundance and Yap1 activation in human squamous cell carcinoma tumors. These findings identify αE-catenin as a tumor suppressor that inhibits Yap1 activity and sequesters it in the cytoplasm.
doi:10.1126/scisignal.2001823
PMCID: PMC3366274  PMID: 21610251
8.  Viral-Associated Trichodysplasia 
Archives of Dermatology  2012;148(2):219-223.
Background
Viral-associated trichodysplasia of immunosuppression is a rare cutaneous eruption that is characterized by follicularly based shiny papules and alopecia with characteristic histopathologic findings of abnormally anagen follicules with excessive inner root sheath differentiation. Prior reports have described the histopathologic characteristics on vertical sections; however, to our knowledge, immunohistochemical analysis of polyomavirus proteins has not been previously performed.
Observations
We discuss the thorough diagnostic evaluation and therapy of an unusual case of viral-associated trichodysplasia due to a newly described human polyomavirus that occurred in a patient with post-treatment chronic lymphocytic leukemia and an abnormal white blood cell count. Unique to our study is the immunohistochemical staining for the polyomavirus middle T antigen, which demonstrated positive staining of cellular inclusions within keratinocytes that compose the inner root sheath. Further evaluation with scanning electron microscopy and polymerase chain reaction analysis of viral DNA confirmed the presence of the virus. Treatment with topical cidofovir resulted in dramatic clinical improvement and hair regrowth.
Conclusions
Several tools, including immunohistochemical staining for the polyomavirus middle T antigen, can be used to identify the pathogenic virus associated with viral-associated trichodysplasia. This case highlights the utility of multiple diagnostic modalities and a robust response to a topical therapeutic agent, cidofovir.
doi:10.1001/archdermatol.2011.1413
PMCID: PMC3346264  PMID: 22351821
9.  NOTCH1 and NOTCH3 coordinate esophageal squamous differentiation through a CSL-dependent transcriptional network 
Gastroenterology  2010;139(6):2113-2123.
Background & Aims
The Notch receptor family regulates cell fate through cell-cell communication. CSL (CBF-1/RBP-jκ, Su(H), Lag-1) drives canonical Notch-mediated gene transcription during cell lineage specification, differentiation and proliferation in the hematopoietic system, the intestine, the pancreas and the skin. However, the functional roles of Notch in esophageal squamous epithelial biology remain unknown.
Methods
Normal esophageal keratinocytes were stimulated with calcium chloride to induce terminal differentiation. The squamous epithelia were reconstituted in organotypic three-dimensional culture, a form of human tissue engineering. Notch was inhibited in culture with a γ-secretase inhibitor or dominant negative mastermind-like1 (DNMAML1). The roles of Notch receptors were evaluated by in vitro gain-of-function and loss-of-function experiments. Additionally, DNMAML1 was targeted to the mouse esophagus by cytokeratin K14 promoter-driven Cre (K14Cre) recombination of Lox-STOP-Lox-DNMAML1. Notch-regulated gene expression was determined by reporter transfection, chromatin immunoprecipitation (ChIP) assays, quantitative reverse-transcription polymerase chain reactions (RT-PCR), Western blotting, immunofluorescence and immunohistochemistry.
Results
NOTCH1 (N1) was activated at the onset of squamous differentiation in the esophagus. Intracellular domain of N1 (ICN1) directly activated NOTCH3 (N3) transcription, inducing HES5 and early differentiation markers such as involucrin (IVL) and cytokeratin CK13 in a CSL-dependent fashion. N3 enhanced ICN1 activity and was required for squamous differentiation. Loss of Notch signaling in K14Cre;DNMAML1 mice perturbed esophageal squamous differentiation and resulted in N3 loss and basal cell hyperplasia.
Conclusions
Notch signaling is important for esophageal epithelial homeostasis. In particular, the crosstalk of N3 with N1 during differentiation provides novel, mechanistic insights into Notch signaling and squamous epithelial biology.
doi:10.1053/j.gastro.2010.08.040
PMCID: PMC2997138  PMID: 20801121
NOTCH1; NOTCH3; esophageal epithelium; squamous differentiation
10.  Decreased Srcasm expression in esophageal squamous cell arcinoma in a Chinese population 
Anticancer research  2010;30(9):3535-3539.
Src-family tyrosine kinases (SFKs) play critical roles in regulating cellular proliferation in epithelial cells, and SFK activity is increased in many human carcinomas. Src-activating and signaling molecule (Srcasm) is a novel SFK substrate that downregulates SFK activityand promotes keratinocyte differentiation. Srcasm has also been to shown to function as an anti-oncogene in the epidermis and its levels are decreased in cutaneous squamous cell carcinoma (SCC). The purpose of this study is to determine if Srcasm levels are decreased in esophageal SCC (ESCC) compared with unremarkable mucosa. Given that Srcasm functions as an anti-onocogene in squamous epithelium, we hypothesized that Srcasm levels should be decreased in esophageal SCCs compared to unremarkable mucosa. To evaluate this hypothesis, we performed protein immunohistochemistry for Srcasm on nine unremarkable esophageal mucosal specimens and twelve esophageal SCCs. Our results show that Srcasm protein staining levels are decreased in esophageal SCC compared to unremarkable mucosa. These data show that the pattern of Srcasm staining inversely correlates with ESCC formation and is consistent with the hypothesis that Srcasm may function as an anti-oncogene in esophageal squamous mucosa.
PMCID: PMC3107990  PMID: 20944134
Src-activating and signaling molecule; Src-family tyrosine kinases; esophageal squamous cell carcinoma
11.  Activation of Src-family Tyrosine Kinases in hyperproliferative epidermal disorders 
Journal of cutaneous pathology  2008;35(3):273-277.
Background
Src-family tyrosine kinases (SFKs) are important regulators of keratinocyte growth and differentiation. In a broad range of cell types, persistent activation of SFKs correlates with increased cell proliferation. In this study, we determined if SFK activity is increased in cutaneous neoplasia and psoriasis, common hyperproliferative epidermal disorders.
Methods
Formalin-fixed tissue sections of unremarkable epidermis, psoriasis, actinic keratoses, squamous cell carcinoma in situ (SCIS), and squamous cell carcinoma (SCC) were subjected to immunohistochemical staining for activated SFKs.
Results
All psoriasis specimens displayed significantly greater staining for activated SFKs than sections of unremarkable skin. In the psoriatic biopsies, the degree of epidermal hyperplasia was proportional to the staining for activated SFKs. All actinic keratoses, SCISs, and SCCs exhibited more prominent staining than sections of unremarkable epidermis. Qualitatively, actinic keratoses displayed weaker staining of activated SFKs than the SCC specimens. No discernable difference in activated SFK staining was seen between in situ and invasive specimens.
Conclusions
This study demonstrates increased staining of activated SFKs in human biopsy specimens of psoriasis and cutaneous neoplasia. These data provide direct evidence for increased activation of SFKs in the pathogenesis of hyperproliferative epidermal disorders.
doi:10.1111/j.1600-0560.2007.00807.x
PMCID: PMC3099403  PMID: 18251740
12.  Srcasm corrects Fyn-induced epidermal hyperplasia by kinase downregulation 
The Journal of biological chemistry  2006;282(2):1161-1169.
Summary
Src-family tyrosine kinases (SFKs) are important regulators of epithelial cell growth and differentiation. Characterization of cellular mechanisms that regulate SFK activity will provide insights into the pathogenesis of diseases associated with increased SFK activity. Keratin 14-Fyn (K14) transgenic mice were derived to characterize the effect of Fyn on epidermal growth and differentiation in vivo. The epidermis of K14-Fyn mice is thickened, manifests prominent scale, and exhibits features consistent with hyperproliferation. Increased epidermal Fyn levels correlate with activation of p44/42 MAP kinases, STAT-3, and PDK-1; key signaling molecules that promote epithelial cell growth.
The Src-activating and signaling molecule (Srcasm) is a substrate of SFKs that becomes tyrosine phosphorylated downstream of the EGF receptor. In vitro, increased Srcasm levels promote activation of endogenous Fyn and keratinocyte differentiation. To study the in vivo effect of Srcasm upon Fyn, double transgenic lines were derived. K14-Fyn/Srcasm transgenic mice did not manifest the hyperproliferative phenotype. In contrast, K14-Fyn/Srcasm-P transgenic mice, that express a non-phosphorylatable Srcasm mutant, maintain the hyperproliferative phenotype. Resolution of the hyper-proliferative phenotype correlated with reduced Fyn levels in vivo in three experimental systems: transgenic mice, primary keratinocytes, and cell lines. Biochemical studies reveal that Srcasm-dependent Fyn downregulation requires Fyn kinase activity, phosphorylation of Srcasm, and the SrcasmGAT domain. Therefore, Srcasm is a novel regulator of Fyn promoting kinase downregulation in a phosphorylation-dependent manner. Srcasm may act as a molecular ‘rheostat’ for activated SFKs, and cellular levels of Srcasm may be important for regulating epithelial hyperproliferation associated with increased SFK activity.
doi:10.1074/jbc.M606583200
PMCID: PMC3099404  PMID: 17046829
13.  Curcuminoids Activate p38 Map Kinases and Promote UVB-Dependent Signaling in Keratinocytes 
Experimental dermatology  2010;19(6):493-500.
Curcuminoids exhibit anti-proliferative properties in many cell lines by modulating signaling pathways to inhibit cell growth. However, the specific effects of curcuminoids on human keratinocytes are not well defined, and this situation impairs mechanistic thinking regarding potential therapeutic uses. We hypothesized that curcuminoids would modulate key growth regulatory pathways in keratinocytes to inhibit cell proliferation. To test this hypothesis, the effects of curcumin and tetrahydrocurcumin (THC) on MAP kinase signaling in keratinoctyes were determined.
Primary human keratinocytes treated with curcumin or THC demonstrated decreased activation of p44/42 MAP kinases but increased levels of activated p38 MAP kinases. These data suggest that curcuminoids specifically activate stress-induced MAP kinases while inhibiting mitogen-induced MAP kinases. Curcuminoids also promote the phosphorylation of p53 on serine 15 in a dose-dependent and p38-dependent manner, suggesting that these compounds may activate p53. The effects of curcuminoids on keratinocytes mirrored some aspects of UVB and could be inhibited by N-acetylcysteine, suggesting that these compounds activate p38 through a mechanism that involves glutathione depletion. Both curcuminoids induced G2/M block and inhibited keratinocyte growth, and THC increased cellular levels of p21, a known p53 transcriptional target.
These data demonstrate that curcuminoids can differentially regulate MAP kinases to inhibit keratinocyte growth while inducing p21. Curcuminoids also synergize with UVB to enhance p53 phosphorylation. The findings provide a rationale for testing curcuminoids in disorders associated with impaired p53 function or in which UVB-treatment is efficacious.
doi:10.1111/j.1600-0625.2010.01081.x
PMCID: PMC3099406  PMID: 20456495
Curcumin; keratinocytes; MAP kinases; p53; UVB
14.  Decreased Srcasm expression in hyperproliferative cutaneous lesions 
Journal of cutaneous pathology  2009;36(3):291-295.
Background
Src-family tyrosine kinases (SFKs) are signaling proteins that regulate keratinocyte proliferation and differentiation. Srcasm is a recently identified molecule that downregulates SFK activity and promotes keratinocyte differentiation. To determine if Srcasm expression correlates with keratinocyte differentiation, we characterized the level of Srcasm expression in some cutaneous lesions that exhibit increased keratinocyte proliferation.
Methods
Formalin-fixed sections of randomly selected seborrheic keratoses and basal cell carcinomas were analyzed for Srcasm and Ki-67 immunohistochemical staining. Anti-Srcasm and anti- Ki-67 staining were performed in parallel.
Results
All seborrheic keratoses displayed decreased Srcasm staining in areas comprised of basaloid keratinocytes that exhibited an increased Ki-67 index. Higher Srcasm staining levels were detected near pseudo-horn cysts where keratinocytes exhibited a lower Ki-67 index. All multicentric and nodular basal cell carcinomas displayed a prominent loss of Srcasm staining in association with a marked increase in Ki-67 staining.
Conclusions
Our results support the hypothesis that Srcasm protein levels are decreased in the hyperproliferative keratinocytes found in seborrheic keratoses and basal cell carcinomas. Increased Srcasm protein levels are detected in keratinocytes undergoing differentiation. Decreased Srcasm levels may be part of the pathophysiologic mechanism in cutaneous lesions exhibiting keratinocyte hyperproliferation.
doi:10.1111/j.1600-0560.2008.01035.x
PMCID: PMC3099410  PMID: 19220627
15.  Renbök Phenomenon and Contact Sensitization in a Patient with Alopecia Universalis 
Archives of dermatology  2010;146(4):422-425.
Background
Immune responses are largely regulated by cytokines secreted by activated T cells. Interactions among these cells are complex, and the interaction between two responses may alter the effect of either response alone. It is established that contact sensitization-induced inflammation can reverse hair loss due to alopecia areata. In parallel, the Renbök phenomenon demonstrates how two distinct autoimmune diseases, psoriasis and alopecia areata, interact to result in clinically active psoriasis suppressing alopecia areata.
Observations
We describe a patient with concurrent psoriasis and alopecia areata universalis with terminal hairs within plaques on his extremities, representing the only normal hair growth on his body. Adjacent biopsies confirmed our clinical suspicion of plaque psoriasis with normal hair follicles and alopecia areata universalis with a peribulbar lymphocytic infiltrate. Our patient’s psoriatic plaques cleared rapidly with nbUVB phototherapy but hair growth at the site was maintained. His scalp alopecia responded to squaric acid contact sensitization therapy.
Conclusions
Our patient represents a natural experiment in whom three distinct but overlapping immune responses favored psoriasis or contact dermatitis over alopecia areata. The precise mechanism responsible for these effects remains unclear; however, based on recent reports, we speculate that cytokine cross-regulation plays a role in competition among these distinct immune responses.
doi:10.1001/archdermatol.2010.42
PMCID: PMC2888038  PMID: 20404233
16.  Srcasm inhibits Fyn-induced cutaneous carcinogenesis with modulation of Notch 1 and p53 
Cancer research  2009;69(24):9439-9447.
Src-family tyrosine kinases (SFKs) regulate cell proliferation, and increased SFK activity is common in human carcinomas, including cutaneous squamous cell carcinomas and its precursors. The elevated SFK activity in cutaneous SCCs was modeled using keratin 14-Fyn Y528F transgenic mice, which spontaneously form punctate keratotic lesions, scaly plaques, and large tumors resembling actinic keratoses (AKs), carcinoma in situ (SCIS), and SCCs, respectively.
Lesional tissue demonstrated increased levels of activated SFKs, PDK-1, STAT-3, and Erk1/2 while Notch 1/NICD protein and transcript levels were decreased. p53 levels also were decreased in SCIS and SCCs.
Raising Srcasm levels using a K14-Fyn Y528F/K14-Srcasm double transgenic model markedly inhibited cutaneous neoplasia. In contrast, increased expression of a non-phosphorylatable Srcasm mutant maintained the neoplastic phenotype. Raising Srcasm levels decreased levels of Fyn, activated SFKs, Erk 1/2, PDK-1, and phospho-STAT3, and raised Notch 1/NICD and p53 levels.
Analysis of human specimens revealed that levels of Fyn and activated SFKs were elevated in SCCs compared with adjacent non-lesional epidermis. In addition, Notch 1 and Srcasm protein and transcript levels were decreased in human SCCs compared to non-lesional epidermis. Therefore, the SCCs produced by the Fyn Y528F mice resemble their human counterparts at the molecular level.
K14-Fyn Y528F mice represent a robust model of cutaneous carcinogenesis that manifests precancerous lesions and SCCs resembling human disease. The Fyn/Srcasm signaling nexus modulates activity of STAT-3, PDK-1, Erk 1/2, Notch 1 and p53. Further study of Fyn and Srcasm should provide insights into the mechanisms regulating keratinocyte proliferation and skin carcinogenesis.
doi:10.1158/0008-5472.CAN-09-2976
PMCID: PMC2794931  PMID: 19934324
17.  The miRNA-Processing Enzyme Dicer Is Essential for the Morphogenesis and Maintenance of Hair Follicles 
Current biology : CB  2006;16(10):1041-1049.
Summary
The discovery that microRNAs (miRNAs) play important roles in regulating gene expression via post-transcriptional repression has revealed a previously unsuspected mechanism controlling development and progenitor-cell function (reviewed in [1, 2]); however, little is known of miRNA functions in mammalian organogenesis. Processing of miRNAs and their assembly into the RNA-induced silencing (RISC) complex requires the essential multifunctional enzyme Dicer [1]. We found that Dicer mRNA and multiple miRNAs are expressed in mouse skin, suggesting roles in skin- and hair-follicle biology. In newborn mice carrying an epidermal-specific Dicer deletion, hair follicles were stunted and hypoproliferative. Hair-shaft and inner-root-sheath differentiation was initiated, but the mutant hair follicles were misoriented and expression of the key signaling molecules Shh and Notch1 was lost by postnatal day 7. At this stage, hair-follicle dermal papillae were observed to evaginate, forming highly unusual structures within the basal epidermis. Normal hair shafts were not produced in the Dicer mutant, and the follicles lacked stem cell markers and degenerated. In contrast to decreased follicular proliferation, the epidermis became hyperproliferative. These results reveal critical roles for Dicer in the skin and implicate miRNAs in key aspects of epidermal and hair-follicle development and function.
doi:10.1016/j.cub.2006.04.005
PMCID: PMC2996092  PMID: 16682203
18.  Activation of beta-catenin signaling programs embryonic epidermis to hair follicle fate 
Development (Cambridge, England)  2008;135(12):2161-2172.
β-catenin signaling is required for hair follicle development, but it is unknown whether its activation is sufficient to globally program embryonic epidermis to hair follicle fate. To address this we mutated endogenous epithelial β-catenin to a dominant active form in vivo. Hair follicle placodes were expanded and induced prematurely in activated β-catenin mutant embryos, but failed to invaginate or form multilayered structures. Eventually, the entire epidermis adopted hair follicle fate, broadly expressing hair shaft keratins in place of epidermal stratification proteins. Mutant embryonic skin was precociously innervated, and displayed prenatal pigmentation, a phenomenon never observed in wild-type controls. Thus β-catenin signaling programs the epidermis towards placode and hair shaft fate at the expense of epidermal differentiation, and activates signals directing pigmentation and innervation. In transcript profiling experiments we identified elevated expression of Sp5, a direct β-catenin target and transcriptional repressor. We show that Sp5 normally localizes to hair follicle placodes and can suppress epidermal differentiation gene expression. We identified the pigmentation regulators Foxn1, Adamsts20 and Kitl, and the neural guidance genes Sema4c, Sema3c, Unc5b and Unc5c, as potential mediators of the effects of β-catenin signaling on pigmentation and innervation. Our data provide evidence for a new paradigm in which, in addition to promoting hair follicle placode and hair shaft fate, β-catenin signaling actively suppresses epidermal differentiation and directs pigmentation and nerve fiber growth. Controlled downregulation of β-catenin signaling is required for normal placode patterning within embryonic ectoderm, hair follicle downgrowth, and adoption of the full range of follicular fates.
doi:10.1242/dev.017459
PMCID: PMC2516408  PMID: 18480165
epidermis; hair follicle; mouse embryo; β-catenin; Wnt
19.  Gene Array Analysis Reveals Changes in Peripheral Nervous System Gene Expression following Stimuli That Result in Reactivation of Latent Herpes Simplex Virus Type 1: Induction of Transcription Factor Bcl-3 
Journal of Virology  2001;75(20):9909-9917.
The earliest events within the peripheral mammalian nervous system that cause herpes simplex virus type 1 (HSV-1) to reactivate from latency are unknown but are highly likely to include altered regulation of cellular transcription factors. Using gene array analysis, we have examined the changes that occur in cellular mRNA levels in mouse trigeminal ganglia following explantation, a stimulus that results in HSV-1 reactivation from latency. We have detected both increased and decreased expression levels of particular cellular transcripts, which include RNAs encoding neuronal factors, transcription factors, and factors involved in the cell cycle. Among the transcription factors that are upregulated is Bcl-3, a coactivator for NFκB. We have confirmed these increases in Bcl-3 transcription levels using reverse transcription-PCR and S1 nuclease protection assays. In addition, we have shown Bcl-3 upregulation at the protein level. Importantly, Bcl-3 RNA levels were found to increase specifically in neuronal cells within the trigeminal ganglia. We discuss a potential role for this factor in upregulating ICP0 transcription, which is an important viral event for initiation of HSV-1 reactivation.
doi:10.1128/JVI.75.20.9909-9917.2001
PMCID: PMC114562  PMID: 11559823

Results 1-19 (19)