Abstract
Desmocollins (Dscs) are desmosomal cadherins that exhibit differentiation-specific patterns of expression in the epidermis. Dsc3 expression is strongest in basal cell layers, whereas Dsc1 is largely confined to upper, terminally differentiating strata. To understand better the processes by which Dsc expression is regulated in the epidermis, we have isolated Dsc3 and Dsc1 5'-flanking DNAs and analysed their activity in primary keratinocytes. In the present study, we found that transcription factors of the CCAAT/enhancer-binding protein family play a role in the regulation of expression of both Dscs and, in so doing, implicate this class of transcription factors in both early and late events in keratinocyte differentiation. We show that Dscs are differentially regulated by C/EBP (CCAAT/enhancer-binding protein) family members, with Dsc3 expression being activated by C/EBPbeta but not C/EBPalpha, and the reverse being the case for Dsc1. Expression of both Dscs is activated by another family member, C/EBPdelta. These results show for the first time how desmosomal cadherin gene expression is regulated and provide a mechanism for the control of other differentiation-specific genes in the epidermis.
Full Text
The Full Text of this article is available as a PDF (403.4 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Adams M. J., Reichel M. B., King I. A., Marsden M. D., Greenwood M. D., Thirlwell H., Arnemann J., Buxton R. S., Ali R. R. Characterization of the regulatory regions in the human desmoglein genes encoding the pemphigus foliaceous and pemphigus vulgaris antigens. Biochem J. 1998 Jan 1;329(Pt 1):165–174. doi: 10.1042/bj3290165. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Agarwal C., Efimova T., Welter J. F., Crish J. F., Eckert R. L. CCAAT/enhancer-binding proteins. A role in regulation of human involucrin promoter response to phorbol ester. J Biol Chem. 1999 Mar 5;274(10):6190–6194. doi: 10.1074/jbc.274.10.6190. [DOI] [PubMed] [Google Scholar]
- Amagai M., Matsuyoshi N., Wang Z. H., Andl C., Stanley J. R. Toxin in bullous impetigo and staphylococcal scalded-skin syndrome targets desmoglein 1. Nat Med. 2000 Nov;6(11):1275–1277. doi: 10.1038/81385. [DOI] [PubMed] [Google Scholar]
- Andersen B., Weinberg W. C., Rennekampff O., McEvilly R. J., Bermingham J. R., Jr, Hooshmand F., Vasilyev V., Hansbrough J. F., Pittelkow M. R., Yuspa S. H. Functions of the POU domain genes Skn-1a/i and Tst-1/Oct-6/SCIP in epidermal differentiation. Genes Dev. 1997 Jul 15;11(14):1873–1884. doi: 10.1101/gad.11.14.1873. [DOI] [PubMed] [Google Scholar]
- Bull Jonathan J., Müller-Röver Sven, Chronnell Catherine M. T., Paus Ralf, Philpott Michael P., McKay Ian A. Contrasting expression patterns of CCAAT/enhancer-binding protein transcription factors in the hair follicle and at different stages of the hair growth cycle. J Invest Dermatol. 2002 Jan;118(1):17–24. doi: 10.1046/j.0022-202x.2001.01629.x. [DOI] [PubMed] [Google Scholar]
- Byrne C. Regulation of gene expression in developing epidermal epithelia. Bioessays. 1997 Aug;19(8):691–698. doi: 10.1002/bies.950190809. [DOI] [PubMed] [Google Scholar]
- Chidgey M., Brakebusch C., Gustafsson E., Cruchley A., Hail C., Kirk S., Merritt A., North A., Tselepis C., Hewitt J. Mice lacking desmocollin 1 show epidermal fragility accompanied by barrier defects and abnormal differentiation. J Cell Biol. 2001 Nov 19;155(5):821–832. doi: 10.1083/jcb.200105009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chitaev N. A., Troyanovsky S. M. Direct Ca2+-dependent heterophilic interaction between desmosomal cadherins, desmoglein and desmocollin, contributes to cell-cell adhesion. J Cell Biol. 1997 Jul 14;138(1):193–201. doi: 10.1083/jcb.138.1.193. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Corbi A. L., Jensen U. B., Watt F. M. The alpha2 and alpha5 integrin genes: identification of transcription factors that regulate promoter activity in epidermal keratinocytes. FEBS Lett. 2000 Jun 2;474(2-3):201–207. doi: 10.1016/s0014-5793(00)01591-x. [DOI] [PubMed] [Google Scholar]
- Descombes P., Schibler U. A liver-enriched transcriptional activator protein, LAP, and a transcriptional inhibitory protein, LIP, are translated from the same mRNA. Cell. 1991 Nov 1;67(3):569–579. doi: 10.1016/0092-8674(91)90531-3. [DOI] [PubMed] [Google Scholar]
- DiPersio C. M., Hodivala-Dilke K. M., Jaenisch R., Kreidberg J. A., Hynes R. O. alpha3beta1 Integrin is required for normal development of the epidermal basement membrane. J Cell Biol. 1997 May 5;137(3):729–742. doi: 10.1083/jcb.137.3.729. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Eckert R. L., Crish J. F., Banks E. B., Welter J. F. The epidermis: genes on - genes off. J Invest Dermatol. 1997 Oct;109(4):501–509. doi: 10.1111/1523-1747.ep12336477. [DOI] [PubMed] [Google Scholar]
- Elias P. M., Matsuyoshi N., Wu H., Lin C., Wang Z. H., Brown B. E., Stanley J. R. Desmoglein isoform distribution affects stratum corneum structure and function. J Cell Biol. 2001 Apr 16;153(2):243–249. doi: 10.1083/jcb.153.2.243. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Eshkind Leonid, Tian Qi, Schmidt Ansgar, Franke Werner W., Windoffer Reinhard, Leube Rudolf E. Loss of desmoglein 2 suggests essential functions for early embryonic development and proliferation of embryonal stem cells. Eur J Cell Biol. 2002 Nov;81(11):592–598. doi: 10.1078/0171-9335-00278. [DOI] [PubMed] [Google Scholar]
- Gadhavi P. L., Greenwood M. D., Strom M., King I. A., Buxton R. S. The regulatory region of the human desmocollin 3 promoter forms a DNA four-way junction. Biochem Biophys Res Commun. 2001 Feb 23;281(2):520–528. doi: 10.1006/bbrc.2001.4375. [DOI] [PubMed] [Google Scholar]
- Garrod D., Chidgey M., North A. Desmosomes: differentiation, development, dynamics and disease. Curr Opin Cell Biol. 1996 Oct;8(5):670–678. doi: 10.1016/s0955-0674(96)80108-6. [DOI] [PubMed] [Google Scholar]
- Green K. J., Gaudry C. A. Are desmosomes more than tethers for intermediate filaments? Nat Rev Mol Cell Biol. 2000 Dec;1(3):208–216. doi: 10.1038/35043032. [DOI] [PubMed] [Google Scholar]
- Hildesheim J., Kühn U., Yee C. L., Foster R. A., Yancey K. B., Vogel J. C. The hSkn-1a POU transcription factor enhances epidermal stratification by promoting keratinocyte proliferation. J Cell Sci. 2001 May;114(Pt 10):1913–1923. doi: 10.1242/jcs.114.10.1913. [DOI] [PubMed] [Google Scholar]
- Hunt D. M., Rickman L., Whittock N. V., Eady R. A., Simrak D., Dopping-Hepenstal P. J., Stevens H. P., Armstrong D. K., Hennies H. C., Küster W. Spectrum of dominant mutations in the desmosomal cadherin desmoglein 1, causing the skin disease striate palmoplantar keratoderma. Eur J Hum Genet. 2001 Mar;9(3):197–203. doi: 10.1038/sj.ejhg.5200605. [DOI] [PubMed] [Google Scholar]
- Hunt D. M., Sahota V. K., Taylor K., Simrak D., Hornigold N., Arnemann J., Wolfe J., Buxton R. S. Clustered cadherin genes: a sequence-ready contig for the desmosomal cadherin locus on human chromosome 18. Genomics. 1999 Dec 15;62(3):445–455. doi: 10.1006/geno.1999.6036. [DOI] [PubMed] [Google Scholar]
- Kljuic A., Christiano A. M. A novel mouse desmosomal cadherin family member, desmoglein 1 gamma. Exp Dermatol. 2003 Feb;12(1):20–29. doi: 10.1034/j.1600-0625.2003.120103.x. [DOI] [PubMed] [Google Scholar]
- Kljuic Ana, Bazzi Hisham, Sundberg John P., Martinez-Mir Amalia, O'Shaughnessy Ryan, Mahoney My G., Levy Moise, Montagutelli Xavier, Ahmad Wasim, Aita Vincent M. Desmoglein 4 in hair follicle differentiation and epidermal adhesion: evidence from inherited hypotrichosis and acquired pemphigus vulgaris. Cell. 2003 Apr 18;113(2):249–260. doi: 10.1016/s0092-8674(03)00273-3. [DOI] [PubMed] [Google Scholar]
- Koch P. J., Mahoney M. G., Ishikawa H., Pulkkinen L., Uitto J., Shultz L., Murphy G. F., Whitaker-Menezes D., Stanley J. R. Targeted disruption of the pemphigus vulgaris antigen (desmoglein 3) gene in mice causes loss of keratinocyte cell adhesion with a phenotype similar to pemphigus vulgaris. J Cell Biol. 1997 Jun 2;137(5):1091–1102. doi: 10.1083/jcb.137.5.1091. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Legraverend C., Antonson P., Flodby P., Xanthopoulos K. G. High level activity of the mouse CCAAT/enhancer binding protein (C/EBP alpha) gene promoter involves autoregulation and several ubiquitous transcription factors. Nucleic Acids Res. 1993 Apr 25;21(8):1735–1742. doi: 10.1093/nar/21.8.1735. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Li M., Chiba H., Warot X., Messaddeq N., Gérard C., Chambon P., Metzger D. RXR-alpha ablation in skin keratinocytes results in alopecia and epidermal alterations. Development. 2001 Mar;128(5):675–688. doi: 10.1242/dev.128.5.675. [DOI] [PubMed] [Google Scholar]
- Li M., Indra A. K., Warot X., Brocard J., Messaddeq N., Kato S., Metzger D., Chambon P. Skin abnormalities generated by temporally controlled RXRalpha mutations in mouse epidermis. Nature. 2000 Oct 5;407(6804):633–636. doi: 10.1038/35036595. [DOI] [PubMed] [Google Scholar]
- Marcozzi C., Burdett I. D., Buxton R. S., Magee A. I. Coexpression of both types of desmosomal cadherin and plakoglobin confers strong intercellular adhesion. J Cell Sci. 1998 Feb;111(Pt 4):495–509. doi: 10.1242/jcs.111.4.495. [DOI] [PubMed] [Google Scholar]
- Marsden M. D., Collins J. E., Greenwood M. D., Adams M. J., Fleming T. P., Magee A. I., Buxton R. S. Cloning and transcriptional analysis of the promoter of the human type 2 desmocollin gene (DSC2). Gene. 1997 Feb 28;186(2):237–247. doi: 10.1016/s0378-1119(96)00715-9. [DOI] [PubMed] [Google Scholar]
- Maytin E. V., Habener J. F. Transcription factors C/EBP alpha, C/EBP beta, and CHOP (Gadd153) expressed during the differentiation program of keratinocytes in vitro and in vivo. J Invest Dermatol. 1998 Mar;110(3):238–246. doi: 10.1046/j.1523-1747.1998.00123.x. [DOI] [PubMed] [Google Scholar]
- Maytin E. V., Lin J. C., Krishnamurthy R., Batchvarova N., Ron D., Mitchell P. J., Habener J. F. Keratin 10 gene expression during differentiation of mouse epidermis requires transcription factors C/EBP and AP-2. Dev Biol. 1999 Dec 1;216(1):164–181. doi: 10.1006/dbio.1999.9460. [DOI] [PubMed] [Google Scholar]
- Merritt Anita J., Berika Mohamed Y., Zhai Wenwu, Kirk Sarah E., Ji Baijing, Hardman Matthew J., Garrod David R. Suprabasal desmoglein 3 expression in the epidermis of transgenic mice results in hyperproliferation and abnormal differentiation. Mol Cell Biol. 2002 Aug;22(16):5846–5858. doi: 10.1128/MCB.22.16.5846-5858.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Niehof M., Kubicka S., Zender L., Manns M. P., Trautwein C. Autoregulation enables different pathways to control CCAAT/enhancer binding protein beta (C/EBP beta) transcription. J Mol Biol. 2001 Jun 15;309(4):855–868. doi: 10.1006/jmbi.2001.4708. [DOI] [PubMed] [Google Scholar]
- North A. J., Bardsley W. G., Hyam J., Bornslaeger E. A., Cordingley H. C., Trinnaman B., Hatzfeld M., Green K. J., Magee A. I., Garrod D. R. Molecular map of the desmosomal plaque. J Cell Sci. 1999 Dec;112(Pt 23):4325–4336. doi: 10.1242/jcs.112.23.4325. [DOI] [PubMed] [Google Scholar]
- North A. J., Chidgey M. A., Clarke J. P., Bardsley W. G., Garrod D. R. Distinct desmocollin isoforms occur in the same desmosomes and show reciprocally graded distributions in bovine nasal epidermis. Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7701–7705. doi: 10.1073/pnas.93.15.7701. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Phillips M. A., Qin Q., Rice R. H. Identification of an involucrin promoter transcriptional response element with activity restricted to keratinocytes. Biochem J. 2000 May 15;348(Pt 1):45–53. [PMC free article] [PubMed] [Google Scholar]
- Pulkkinen L., Choi Y. W., Kljuic A., Uitto J., Mahoney M. G. Novel member of the mouse desmoglein gene family: Dsg1-beta. Exp Dermatol. 2003 Feb;12(1):11–19. doi: 10.1034/j.1600-0625.2003.120102.x. [DOI] [PubMed] [Google Scholar]
- Ramji Dipak P., Foka Pelagia. CCAAT/enhancer-binding proteins: structure, function and regulation. Biochem J. 2002 Aug 1;365(Pt 3):561–575. doi: 10.1042/BJ20020508. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rickman L., Simrak D., Stevens H. P., Hunt D. M., King I. A., Bryant S. P., Eady R. A., Leigh I. M., Arnemann J., Magee A. I. N-terminal deletion in a desmosomal cadherin causes the autosomal dominant skin disease striate palmoplantar keratoderma. Hum Mol Genet. 1999 Jun;8(6):971–976. doi: 10.1093/hmg/8.6.971. [DOI] [PubMed] [Google Scholar]
- Ron D., Habener J. F. CHOP, a novel developmentally regulated nuclear protein that dimerizes with transcription factors C/EBP and LAP and functions as a dominant-negative inhibitor of gene transcription. Genes Dev. 1992 Mar;6(3):439–453. doi: 10.1101/gad.6.3.439. [DOI] [PubMed] [Google Scholar]
- Runswick S. K., O'Hare M. J., Jones L., Streuli C. H., Garrod D. R. Desmosomal adhesion regulates epithelial morphogenesis and cell positioning. Nat Cell Biol. 2001 Sep;3(9):823–830. doi: 10.1038/ncb0901-823. [DOI] [PubMed] [Google Scholar]
- Seitz C. S., Lin Q., Deng H., Khavari P. A. Alterations in NF-kappaB function in transgenic epithelial tissue demonstrate a growth inhibitory role for NF-kappaB. Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2307–2312. doi: 10.1073/pnas.95.5.2307. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Silos S. A., Tamai K., Li K., Kivirikko S., Kouba D., Christiano A. M., Uitto J. Cloning of the gene for human pemphigus vulgaris antigen (desmoglein 3), a desmosomal cadherin. Characterization of the promoter region and identification of a keratinocyte-specific cis-element. J Biol Chem. 1996 Jul 19;271(29):17504–17511. doi: 10.1074/jbc.271.29.17504. [DOI] [PubMed] [Google Scholar]
- Smith C., Berry M., Clarke W. E., Logan A. Differential expression of fibroblast growth factor-2 and fibroblast growth factor receptor 1 in a scarring and nonscarring model of CNS injury in the rat. Eur J Neurosci. 2001 Feb;13(3):443–456. doi: 10.1046/j.1460-9568.2001.01400.x. [DOI] [PubMed] [Google Scholar]
- Tselepis C., Chidgey M., North A., Garrod D. Desmosomal adhesion inhibits invasive behavior. Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8064–8069. doi: 10.1073/pnas.95.14.8064. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Whittock Neil Vincent. Genomic sequence analysis of the mouse desmoglein cluster reveals evidence for six distinct genes: characterization of mouse DSG4, DSG5, and DSG6. J Invest Dermatol. 2003 Jun;120(6):970–980. doi: 10.1046/j.1523-1747.2003.12257.x. [DOI] [PubMed] [Google Scholar]
- Zhu S., Oh H. S., Shim M., Sterneck E., Johnson P. F., Smart R. C. C/EBPbeta modulates the early events of keratinocyte differentiation involving growth arrest and keratin 1 and keratin 10 expression. Mol Cell Biol. 1999 Oct;19(10):7181–7190. doi: 10.1128/mcb.19.10.7181. [DOI] [PMC free article] [PubMed] [Google Scholar]