Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1996 Jun;73(11):1347–1355. doi: 10.1038/bjc.1996.257

Expression of Mad, an antagonist of Myc oncoprotein function, in differentiating keratinocytes during tumorigenesis of the skin.

A Lymboussaki 1, A Kaipainen 1, E Hatva 1, I Västrik 1, L Jeskanen 1, M Jalkanen 1, S Werner 1, F Stenbäck 1, R Alitalo 1
PMCID: PMC2074494  PMID: 8645578

Abstract

The Myc oncoprotein is associated with cell proliferation and is often down-regulated during cell differentiation. The related Mad transcription factor, which antagonises Myc activity, is highly expressed in epidermal keratinocytes. Mad also inhibits cell proliferation in vitro. To study Mad expression in keratinocyte proliferation and differentiation, we have analysed Mad RNA expression in regenerating and hyperproliferative epidermal lesions and epidermal tumours of varying degrees of differentiation using the RNA in situ hybridisation and RNAase protection techniques. Mad was strongly expressed in differentiating suprabasal keratinocytes in healing dermal wounds and in benign hyperproliferative conditions, but also in squamous cell carcinomas, in which the keratinocytes retain their differentiation potential. However, Mad expression was lost in palisading basal carcinoma cells and poorly differentiated squamous cell carcinomas, which lacked the epithelial differentiation marker syndecan-1. We therefore suggest that Mad expression is closely associated with epithelial cell differentiation, and that this association is retained in epithelial tumours of the skin.

Full text

PDF
1347

Images in this article

1348Figure 1
on p.1348
1349Figure 2
on p.1349
1350Figure 3
on p.1350
1351Figure 4
on p.1351
1352Figure 5
on p.1352
1353Figure 6
on p.1353

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Amati B., Littlewood T. D., Evan G. I., Land H. The c-Myc protein induces cell cycle progression and apoptosis through dimerization with Max. EMBO J. 1993 Dec 15;12(13):5083–5087. doi: 10.1002/j.1460-2075.1993.tb06202.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ayer D. E., Eisenman R. N. A switch from Myc:Max to Mad:Max heterocomplexes accompanies monocyte/macrophage differentiation. Genes Dev. 1993 Nov;7(11):2110–2119. doi: 10.1101/gad.7.11.2110. [DOI] [PubMed] [Google Scholar]
  3. Bjelogrlic N. M., Mäkinen M., Stenbäck F., Vähäkangas K. Benzo[a]pyrene-7,8-diol-9,10-epoxide-DNA adducts and increased p53 protein in mouse skin. Carcinogenesis. 1994 Apr;15(4):771–774. doi: 10.1093/carcin/15.4.771. [DOI] [PubMed] [Google Scholar]
  4. Blackwood E. M., Eisenman R. N. Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc. Science. 1991 Mar 8;251(4998):1211–1217. doi: 10.1126/science.2006410. [DOI] [PubMed] [Google Scholar]
  5. Bremner R., Kemp C. J., Balmain A. Induction of different genetic changes by different classes of chemical carcinogens during progression of mouse skin tumors. Mol Carcinog. 1994 Oct;11(2):90–97. doi: 10.1002/mc.2940110206. [DOI] [PubMed] [Google Scholar]
  6. Cantley L. C., Auger K. R., Carpenter C., Duckworth B., Graziani A., Kapeller R., Soltoff S. Oncogenes and signal transduction. Cell. 1991 Jan 25;64(2):281–302. doi: 10.1016/0092-8674(91)90639-g. [DOI] [PubMed] [Google Scholar]
  7. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  8. Elenius K., Vainio S., Laato M., Salmivirta M., Thesleff I., Jalkanen M. Induced expression of syndecan in healing wounds. J Cell Biol. 1991 Aug;114(3):585–595. doi: 10.1083/jcb.114.3.585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fuchs E. Epidermal differentiation and keratin gene expression. J Cell Sci Suppl. 1993;17:197–208. doi: 10.1242/jcs.1993.supplement_17.28. [DOI] [PubMed] [Google Scholar]
  10. Fuchs E. Epidermal differentiation: the bare essentials. J Cell Biol. 1990 Dec;111(6 Pt 2):2807–2814. doi: 10.1083/jcb.111.6.2807. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hurlin P. J., Quéva C., Koskinen P. J., Steingrímsson E., Ayer D. E., Copeland N. G., Jenkins N. A., Eisenman R. N. Mad3 and Mad4: novel Max-interacting transcriptional repressors that suppress c-myc dependent transformation and are expressed during neural and epidermal differentiation. EMBO J. 1995 Nov 15;14(22):5646–5659. doi: 10.1002/j.1460-2075.1995.tb00252.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Inki P., Joensuu H., Grénman R., Klemi P., Jalkanen M. Association between syndecan-1 expression and clinical outcome in squamous cell carcinoma of the head and neck. Br J Cancer. 1994 Aug;70(2):319–323. doi: 10.1038/bjc.1994.300. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Jalkanen M., Nguyen H., Rapraeger A., Kurn N., Bernfield M. Heparan sulfate proteoglycans from mouse mammary epithelial cells: localization on the cell surface with a monoclonal antibody. J Cell Biol. 1985 Sep;101(3):976–984. doi: 10.1083/jcb.101.3.976. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Korhonen M., Stenbäck F. Adenocarcinoma metastatic to the uterine cervix. Gynecol Obstet Invest. 1984;17(2):57–65. doi: 10.1159/000299123. [DOI] [PubMed] [Google Scholar]
  15. Larsson L. G., Pettersson M., Oberg F., Nilsson K., Lüscher B. Expression of mad, mxi1, max and c-myc during induced differentiation of hematopoietic cells: opposite regulation of mad and c-myc. Oncogene. 1994 Apr;9(4):1247–1252. [PubMed] [Google Scholar]
  16. Lüscher B., Eisenman R. N. New light on Myc and Myb. Part I. Myc. Genes Dev. 1990 Dec;4(12A):2025–2035. doi: 10.1101/gad.4.12a.2025. [DOI] [PubMed] [Google Scholar]
  17. Mali M., Jaakkola P., Arvilommi A. M., Jalkanen M. Sequence of human syndecan indicates a novel gene family of integral membrane proteoglycans. J Biol Chem. 1990 Apr 25;265(12):6884–6889. [PubMed] [Google Scholar]
  18. Morgenbesser S. D., DePinho R. A. Use of transgenic mice to study myc family gene function in normal mammalian development and in cancer. Semin Cancer Biol. 1994 Feb;5(1):21–36. [PubMed] [Google Scholar]
  19. Stenbäck F. Life history and histopathology of ultraviolet light-induced skin tumors. Natl Cancer Inst Monogr. 1978 Dec;(50):57–70. [PubMed] [Google Scholar]
  20. Tokunaga K., Taniguchi H., Yoda K., Shimizu M., Sakiyama S. Nucleotide sequence of a full-length cDNA for mouse cytoskeletal beta-actin mRNA. Nucleic Acids Res. 1986 Mar 25;14(6):2829–2829. doi: 10.1093/nar/14.6.2829. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Västrik I., Kaipainen A., Penttilä T. L., Lymboussakis A., Alitalo R., Parvinen M., Alitalo K. Expression of the mad gene during cell differentiation in vivo and its inhibition of cell growth in vitro. J Cell Biol. 1995 Mar;128(6):1197–1208. doi: 10.1083/jcb.128.6.1197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Västrik I., Koskinen P. J., Alitalo R., Mäkelä T. P. Alternative mRNA forms and open reading frames of the max gene. Oncogene. 1993 Feb;8(2):503–507. [PubMed] [Google Scholar]
  23. Werner S., Peters K. G., Longaker M. T., Fuller-Pace F., Banda M. J., Williams L. T. Large induction of keratinocyte growth factor expression in the dermis during wound healing. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):6896–6900. doi: 10.1073/pnas.89.15.6896. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Wilkinson D. G., Bailes J. A., Champion J. E., McMahon A. P. A molecular analysis of mouse development from 8 to 10 days post coitum detects changes only in embryonic globin expression. Development. 1987 Apr;99(4):493–500. doi: 10.1242/dev.99.4.493. [DOI] [PubMed] [Google Scholar]
  25. Wilkinson D. G., Bailes J. A., McMahon A. P. Expression of the proto-oncogene int-1 is restricted to specific neural cells in the developing mouse embryo. Cell. 1987 Jul 3;50(1):79–88. doi: 10.1016/0092-8674(87)90664-7. [DOI] [PubMed] [Google Scholar]
  26. Yuspa S. H., Kilkenny A., Cheng C., Roop D., Hennings H., Kruszewski F., Lee E., Strickland J., Greenhalgh D. A. Alterations in epidermal biochemistry as a consequence of stage-specific genetic changes in skin carcinogenesis. Environ Health Perspect. 1991 Jun;93:3–10. doi: 10.1289/ehp.91933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Yuspa S. H. The pathogenesis of squamous cell cancer: lessons learned from studies of skin carcinogenesis--thirty-third G. H. A. Clowes Memorial Award Lecture. Cancer Res. 1994 Mar 1;54(5):1178–1189. [PubMed] [Google Scholar]
  28. Zervos A. S., Gyuris J., Brent R. Mxi1, a protein that specifically interacts with Max to bind Myc-Max recognition sites. Cell. 1993 Jan 29;72(2):223–232. doi: 10.1016/0092-8674(93)90662-a. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES