Skip to main content
SpringerLink
Log in

Expression of Developmentally Regulated Transcription Factors in Merkel Cell Carcinoma

  • Conference paper
The Merkel Cell

Summary

We have examined a number of developmentally regulated transcription factors for expression in Merkel cells and MCC cell lines and demonstrated that their expression patterns may be prognostic in MCC. We have shown that human Merkel cells from adult scalp hair follicle and from neonatal foreskin epidermal sheets express Brn-3c and HATH1. In addition, results demonstrate that the novel Merkel binding activity complex MNF contains Brn-3c. Moreover, Classic lines which retain neuroendocrine phenotype, are slow growing in culture, grow in suspension and are thought to be less aggressive, retain Brn-2, Brn-3c and HATH1 expression, whereas Variant suspension lines which no longer express NE markers retain Brn-2 and Brn-3c expression, but lack HATH1. Further, Type IV Variant lines which grow as adherent monolayers have shorter doubling times, are more radiation-resistant and have higher cloning efficiencies in soft agar, all thought to be indicative of aggressive tumours, have reduced or no Brn-2 proteins and lack expression of Brn-3c and HATH1 transcription factors.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Armstrong BK and Kricker A (2001) The epidemiology of UV-induced skin cancer. J Photochem Photobiol B Biol 63: 8 - 18

    Article  CAS  Google Scholar 

  • Atanasoski S, Schreiber E, Fontana A, Herr W (1997) N-Oct 5 is generated by in vitro proteolysis of the neural POU-domain protein N-Oct 3. Oncogene 14: 1287 - 1294

    Article  PubMed  CAS  Google Scholar 

  • Ball DW, Azzoli CG, Baylin SB, Chi D, Dou S, Donis-Keller H, Cumaraswamy A, Borges M, Nelkin BD (1993) Identification of a human achaete-scute homolog highly expressed in neuroendocrine tumors. Proc Natl Acad Sci USA 90: 5648 - 5652

    Article  PubMed  CAS  Google Scholar 

  • Ben-Arie N, Hassan BA, Bermingham NA, Malicki DM, Armstrong D, Matzuk M, Bellen HJ, Zoghbi HY (2000) Functional conservation of atonal and Mathl in the CNS and PNS. Development 127: 1039 - 1048

    PubMed  CAS  Google Scholar 

  • Bermingham NA, Hassan BA, Price SD, Vollrath MA, Ben-Arie N, Eatock RA, Bellen HJ, Lysakowski A, Zoghbi HY (1999) Mathl: an essential gene for the generation of inner ear hair cells. Science 284: 1837 - 1841

    Article  PubMed  CAS  Google Scholar 

  • Budhram-Mahadeo V, Morris PJ, Smith MD, Midgley CA, Boxer LM, Latchman DS (1999a) p53 suppresses the activation of the Bcl-2 promoter by the Brn-3a POU family transcription factor. J Biol Chem 274: 15237 - 15244

    Google Scholar 

  • Budhram-Mahadeo V, Ndisang D, Ward T, Weber BL, Latchman DS (1999b) The Brn-3b POU family transcription factor represses expression of the BRCA-1 anti-oncogene in breast cancer cells. Oncogene 18: 6684 - 6691

    Article  PubMed  CAS  Google Scholar 

  • Carney DN, Gazdar AF, Bepler G, Guccion JG, Marangos PJ, Moody TW, Zweig MH, Minna JD (1985) Establishment and identification of small cell lung cancer cell lines having classic and variant features. Cancer Res 45: 2913 - 2923

    PubMed  CAS  Google Scholar 

  • Chen H, Thiagalingam A, Chopra H, Borges MW, Feder JN, Nelkin BD, Baylin SB, Ball DW (1997) Conservation of the Drosophila lateral inhibition pathway in human lung cancer: a hairy-related protein (HES-1) directly represses achaete-scute homolog-1 expression. Proc Natl Acad Sci USA 94: 5355 - 5360

    Article  PubMed  CAS  Google Scholar 

  • Collum RG, Fisher PE, Datta M, Mellis S, Thiele C, Huebner K, Croce CM, Israel MA, Theil T, Moroy T (1992) A novel POU homeodomain gene specifically expressed in cells of the developing mammalian nervous system. Nucleic Acids Res 20: 4919 - 4925

    Article  PubMed  CAS  Google Scholar 

  • Compton CC, Regauer S, Seiler GR, Landry DB (1990) Human Merkel cell regeneration in skin derived from cultured keratinocyte grafts. Lab Invest 63: 233 - 241

    PubMed  CAS  Google Scholar 

  • Eberl DF, Hardy RW, Kernan MJ (2000) Genetically similar transduction mechanisms for touch and hearing in Drosophila. J Neurosci 20: 5981 - 5988

    PubMed  CAS  Google Scholar 

  • Erkman L, McEvilly RJ, Luo L, Ryan AK, Hooshmand F, O’Connell SM, Keithley EM, Rapaport DH, Ryan AF, Rosenfeld MG (1996) Role of transcription factors Brn-3.1 and Brn-3.2 in auditory and visual system development. Nature 381: 603 - 606

    Article  PubMed  CAS  Google Scholar 

  • Erkman L, Yates PA, McLaughlin T, McEvilly RJ, Whisenhunt T, O’Connell SM, Krones AI, Kirby MA, Rapaport DH, Bermingham JR, O’Leary DD, Rosenfeld MG (2000) A POU domain transcription factor-dependent program regulates axon pathfinding in the vertebrate visual system. Neuron 28: 779 - 792

    Article  PubMed  CAS  Google Scholar 

  • Gazdar AF, Carney DN, Nau MM, Minna JD (1985) Characterization of variant subclasses of cell lines derived from small cell lung cancer having distinctive biochemical, morphological, and growth properties. Cancer Res 45: 2924 - 2930

    PubMed  CAS  Google Scholar 

  • Hara Y, Rovescalli AC, Kim Y, Nirenberg M (1992) Structure and evolution of four POU domain genes expressed in mouse brain. Proc Natl Acad Sci USA 89: 3280 - 3284

    Article  PubMed  CAS  Google Scholar 

  • Hartschuh W, Weihe E, Egner U (1989) Chromogranin A in the mammalian Merkel cell: cellular and subcellular distribution. J Invest Dermatol 93: 641 - 648

    Article  PubMed  CAS  Google Scholar 

  • He X, Treacy MN, Simmons DM, Ingraham HA, Swanson LW, Rosenfeld MG (1989) Expression of a large family of POU-domain regulatory genes in mammalian brain development. Nature 340: 35 - 41

    Article  PubMed  CAS  Google Scholar 

  • Helms AW, Abney AL, Ben-Arie N, Zoghbi HY, Johnson JE (2000) Autoregulation and multiple enhancers control Mathl expression in the developing nervous system. Development 127: 1185 - 1196

    PubMed  CAS  Google Scholar 

  • Herr W, Cleary MA (1995) The POU domain: versatility in transcriptional regulation by a flexible two-in-one DNA-binding domain. Genes Dev 9: 1679 - 1693

    Article  PubMed  CAS  Google Scholar 

  • Herr W, Sturm RA, Clerc RG, Corcoran LM, Baltimore D, Sharp PA, Ingraham HA, Rosenfeld MG, Finney M, Ruvkun G (1988) The POU domain: a large conserved region in the mammalian pit-1, oct-1, oct-2, and Caenorhabditis elegans unc-86 gene products. Genes Dev 2: 1513 - 1516

    Article  PubMed  CAS  Google Scholar 

  • Huang EJ, Zang K, Schmidt A, Saulys A, Xiang M, Reichardt LF (1999) POU domain factor Brn-3a controls the differentiation and survival of trigeminal neurons by regulating Trk receptor expression. Development 126: 2869 - 2882

    PubMed  CAS  Google Scholar 

  • Isaka F, Ishibashi M, Taki W, Hashimoto N, Nakanishi S, Kageyama R (1999) Ectopic expression of the bHLH gene Mathl disturbs neural development. Eur J Neurosci 11: 2582 - 2588

    Article  PubMed  CAS  Google Scholar 

  • Latchman DS (1999) POU family transcription factors in the nervous system. J Cell Physiol 179: 126 - 133

    Article  PubMed  CAS  Google Scholar 

  • Leblond-Francillard M, Picon A, Bertagna X, de Keyzer Y (1997) High expression of the POU factor Brn3a in aggressive neuroendocrine tumors. J Clin Endocrinol Metab 82: 89 - 94

    Article  PubMed  CAS  Google Scholar 

  • Leonard JH, Bell JR, Kearsley JH (1993) Characterization of cell lines established from Merkel-cell (“small-cell”) carcinoma of the skin. Int J Cancer 55: 803 - 810

    Article  PubMed  CAS  Google Scholar 

  • Leonard JH, Dash P, Holland P, Kearsley JH, Bell JR (1995a) Characterisation of four Merkel cell carcinoma adherent cell lines. Int J Cancer 60: 100 - 107

    Article  PubMed  CAS  Google Scholar 

  • Leonard JH, Ramsay JR, Kearsley JH, Birrell GW (1995b) Radiation sensitivity of Merkel cell carcinoma cell lines. Int J Radiat Oncol Biol Phys 32: 1401 - 1407

    Article  PubMed  CAS  Google Scholar 

  • Leonard JH, Cook AL, Van Gele M, Boyle G, Inglis KJ, Speleman F, Sturm RA (2002) Proneoral and proendocrine transcription factor expression in cutaneous mechanoreceptors ( Merkel) cell and Merkel cell carcinoma. Int J Cancer 102: 103-110

    Google Scholar 

  • Meeuwissen JA, Bourne RG, Kearsley JH (1995) The importance of postoperative radiation therapy in the treatment of Merkel cell carcinoma. Int J Radiat Oncol Biol Phys 31: 325 - 331

    Article  PubMed  CAS  Google Scholar 

  • Moll I, Kuhn C, Moll R (1995) Cytokeratin 20 is a general marker of cutaneous Merkel cells while certain neuronal proteins are absent. J Invest Dermatol 104: 910 - 915

    Article  PubMed  CAS  Google Scholar 

  • Moll I, Zieger W, Schmelz M (1996) Proliferative Merkel cells were not detected in human skin. Arch Dermatol Res 288: 184 - 187

    Article  PubMed  CAS  Google Scholar 

  • Monk M, Holding C (2001) Human embryonic genes re-expressed in cancer cells. Oncogene 20: 8085 - 8091

    Article  PubMed  CAS  Google Scholar 

  • Muller U, Littlewood-Evans A (2001) Mechanisms that regulate mechanosensory hair cell differentiation. Trends Cell Biol 11: 334 - 342

    Article  PubMed  CAS  Google Scholar 

  • Ndisdang D, Morris PJ, Chapman C, Ho L, Singer A, Latchman DS (1998) The HPVactivating cellular transcription factor Brn-3a is overexpressed in CIN3 cervical lesions. J Clin Invest 101: 1687 - 1692

    Article  PubMed  CAS  Google Scholar 

  • Popp S, Waltering S, Herbst C, Moll I, Boukamp P (2002) UV-B-type mutations and chromosomal imbalances indicate common pathways for the development of Merkel and skin squamous cell carcinomas. Int J Cancer 99: 352 - 360

    Article  PubMed  CAS  Google Scholar 

  • Przyborski SA, Morton IE, Wood A, Andrews PW (2000) Developmental regulation of neurogenesis in the pluripotent human embryonal carcinoma cell line NTERA-2. Eur J Neurosci 12: 3521 - 3528

    Article  PubMed  CAS  Google Scholar 

  • Rosenfeld MG (1991) POU-domain transcription factors: pou-er-ful developmental regulators. Genes Dev 5: 897 - 907

    Article  PubMed  CAS  Google Scholar 

  • Schöler HR, Hatzopoulos AK, Balling R, Suzuki N, Gruss P (1989) A family of octamerspecific proteins present during mouse embryogenesis: evidence for germline-specific expression of an Oct factor. EMBO J 8: 2543 - 2550

    PubMed  Google Scholar 

  • Schreiber E, Himmelmann A, Malipiero U, Tobler A, Stahel R, Fontana A (1992) Human small cell lung cancer expresses the octamer DNA-binding and nervous system specific transcription factor N-Oct-3 (brain-2). Cancer Res 52: 6121 - 6124

    PubMed  CAS  Google Scholar 

  • Schreiber E, Merchant RE, Wiestler OD, Fontana A (1994) Primary brain tumors differ in their expression of octamer deoxyribonucleic acid-binding transcription factors from long-term cultured glioma cell lines. Neurosurgery 34: 129 - 135

    Article  PubMed  CAS  Google Scholar 

  • Siskind V, Aitken J, Green A, Martin N (2002) Sun exposure and interaction with family history in risk of melanoma, Queensland, Australia. Int J Cancer 97: 90-95

    Google Scholar 

  • Smith AG, Brightwell G, Smit SE, Parsons PG, Sturm RA (1998) Redox regulation of Brn2/N-Oct-3 POU domain DNA binding activity and proteolytic formation of N-Oct-5 during melanoma cell nuclear extraction. Melanoma Res 8: 2 - 10

    Article  PubMed  CAS  Google Scholar 

  • Sturm RA, Herr W (1988) The POU domain is a bipartite DNA-binding structure. Nature 336: 601 - 604

    Article  PubMed  CAS  Google Scholar 

  • Sturm RA, Das G, Herr W (1988) The ubiquitous octamer-binding protein Oct-1 contains a POU domain with a homeo box subdomain. Genes Dev 2: 1582 - 1599

    Article  PubMed  CAS  Google Scholar 

  • Theil T, McLean-Hunter S, Zornig M, Moroy T (1993) Mouse Brn-3 family of POU transcription factors: a new aminoterminal domain is crucial for the oncogenic activity of Brn-3a. Nucleic Acids Res 21: 5921 - 5929

    Article  PubMed  CAS  Google Scholar 

  • Theil T, Rodel B, Spiegelhalter F, Moroy T (1995) Short isoform of POU factor Brn-3b can form a heterodimer with Brn-3a that is inactive for octamer motif binding. J Biol Chem 270: 30958 - 30964

    Article  PubMed  CAS  Google Scholar 

  • Thomson JA, Parsons PG, Sturm RA (1993) In vivo and in vitro expression of octamer binding proteins in human melanoma metastases, brain tissue, and fibroblasts. Pigment Cell Res 6: 13 - 22

    Article  PubMed  CAS  Google Scholar 

  • Thomson JA, Leonard JH, McGregor K, Sturm RA, Parsons PG (1994) A nonconsensus octamer-recognition sequence ( TAATGARAT-motif) identifies a novel DNA binding protein in human Merkel cell carcinoma cell lines. Int J Cancer 58: 285-290

    Google Scholar 

  • Thomson JA, Murphy K, Baker E, Sutherland GR, Parsons PG, Sturm RA, Thomson F (1995) The brn-2 gene regulates the melanocytic phenotype and tumorigenic potential of human melanoma cells. Oncogene 11: 691 - 700

    PubMed  CAS  Google Scholar 

  • Trieu M, Rhee JM, Fedtsova N, Turner EE (1999) Autoregulatory sequences are revealed by complex stability screening of the mouse brn-3.0 locus. J Neurosci 19: 6549 - 6558

    PubMed  CAS  Google Scholar 

  • Vahava O, Morell R, Lynch ED, Weiss S, Kagan ME, Ahituv N, Morrow JE, Lee MK, Skvorak AB, Morton CC, Blumenfeld A, Frydman M, Friedman TB, King MC, Avraham KB (1998) Mutation in transcription factor POU4F3 associated with inherited progressive hearing loss in humans. Science 279: 1950 - 1954

    Article  PubMed  CAS  Google Scholar 

  • Van Gele M, Kaghad M, Leonard J, Van Roy N, Naeyaert JM, Geerts ML, Van Belle S, Cocquyt V, Bridge J, Sciot R, De Wolf-Peeters C, De Paepe A, Caput D, Speleman F (2000) Mutation analysis of P73 and TP53 in Merkel cell carcinoma. Br J Cancer 82: 23 - 826

    Google Scholar 

  • Xiang M (1998) Requirement for Brn-3b in early differentiation of postmitotic retinal ganglion cell precursors. Dev Biol 197: 55 - 169

    Article  Google Scholar 

  • Xiang M, Zhou L, Macke JP, Yoshioka T, Hendry SH, Eddy RL, Shows TB, Nathans J (1995) The Brn-3 family of POU-domain factors: primary structure, binding specificity, and expression in subsets of retinal ganglion cells and somatosensory neurons. J Neurosci 15: 762 - 4785

    Google Scholar 

  • Xiang M, Gan L, Li D, Chen ZY, Zhou L, O’Malley BW Jr, Klein W, Nathans J (1997) Essential role of POU-domain factor Brn-3c in auditory and vestibular hair cell development. Proc Natl Acad Sci USA 94: 9445 - 9450

    Article  PubMed  CAS  Google Scholar 

  • Xiang M, Gao WQ, Hasson T, Shin JJ (1998) Requirement for Brn-3c in maturation and survival, but not in fate determination of inner ear hair cells. Development 125: 9353946

    Google Scholar 

  • Yang Q, Bermingham NA, Finegold MJ, Zoghbi HY (2001) Requirement of Mathl for secretory cell lineage commitment in the mouse intestine. Science 294: 155 - 2158

    Article  Google Scholar 

  • Youl P, Aitken J, Hayward N, Hogg D, Liu L, Lassam N, Martin N, Green A (2002) Melanoma in adolescents: a case-control study of risk factors in Queensland, Australia. Int J Cancer 98: 2-98

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Queensland Radium Institute Research Unit, Queensland Institute of Medical Research, Brisbane, Queensland, Australia

    J. H. Leonard, A. L. Cook & R. A. Sturm

  2. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia

    A. L. Cook

  3. Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium

    M. Van Gele & F. Speleman

Authors
  1. J. H. Leonard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. L. Cook
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Van Gele
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F. Speleman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R. A. Sturm
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Institute of Functional Morphology, University of Hamburg, UKE, Martinistrasse 52, 20246, Hamburg, Germany

    Klaus I. Baumann  & Zdenek Halata  & 

  2. Department of Dermatology and Venerology, University of Hamburg, UKE, Martinistrasse 52, 20246, Hamburg, Germany

    Ingrid Moll

Rights and permissions

Reprints and permissions

Copyright information

© 2003 Springer-Verlag Berlin Heidelberg

About this paper

Cite this paper

Leonard, J.H., Cook, A.L., Van Gele, M., Speleman, F., Sturm, R.A. (2003). Expression of Developmentally Regulated Transcription Factors in Merkel Cell Carcinoma. In: Baumann, K.I., Halata, Z., Moll, I. (eds) The Merkel Cell. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-10358-6_30

Download citation

  • DOI: https://doi.org/10.1007/978-3-662-10358-6_30

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-05574-4

  • Online ISBN: 978-3-662-10358-6

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation