Dynamic regulation of the human dopachrome tautomerase promoter by MITF, ER-α and chromatin remodelers during proliferation and senescence of human melanocytes

Denise J. Schwahn, Nikolai A. Timchenko, Shigeki Shibahara, Estela E. Medrano

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)


Senescent cells are known to display altered gene expression of differentiation-associated genes. We have previously demonstrated that the melanocyte transcriptional regulator microphthalmia-associated protein (MITF) is down-regulated in senescent melanocytes. Since virtually nothing is known regarding the differentiated function of senescent melanocytes, we analyzed the transcriptional regulation of Dopachrome tautomerase (DCT), a member of the tyrosinase gene family, in proliferating and in senescent human melanocytes. Computational analysis of the region containing the M-box that includes the MITF CATGTG binding motif demonstrated that this sequence overlaps with the estrogen receptor alpha (ER-α), USF-1, TFE-3, IsI-1 and AP-1 binding elements. Electrophoresis gel-shift analysis using an oligonucleotide containing MITF and ERE elements identified MITF and ER-α complexes in proliferating melanocytes, whereas only ER-α complexes were detected in senescent cells. Importantly, a promoter-reporter analysis demonstrated that the coactivator p300/CBP switched MITF from a repressor to an activator of DCT transcription. p300/CBP was also required by ER-α and MITF to induce high, synergistic activation of the DCT promoter. We have also found that transcription of the DCT gene is differentially regulated by major melanocyte mitogens. In contrast to the activating effect of cAMP inducers, 12-O-tetradecanoylphorbolacetate (TPA) was a potent repressor of DCT transcription, suggesting that this gene can be differentially regulated by multiple environmental signals and promoter context. In support of this conclusion, trichostatin A, a histone deacetylase inhibitor, counteracted the TPA-mediated repression, and restored high levels of DCT protein in cultured melanocytes. We conclude that senescent melanocytes display dramatic changes in the expression of differentiation-related proteins; such changes may in turn result in altered melanocyte function and survival to environmental stresses.

Original languageEnglish
Pages (from-to)203-213
Number of pages11
JournalPigment Cell Research
Issue number3
Publication statusPublished - 2005 Jun
Externally publishedYes


  • Cellular senescence
  • Histone deacetylases
  • Islet-1
  • Microphthalmia
  • Tyrosinase-related protein-2
  • USF-1

ASJC Scopus subject areas

  • Agronomy and Crop Science
  • Plant Science
  • Developmental Biology
  • Clinical Biochemistry
  • Cell Biology


Dive into the research topics of 'Dynamic regulation of the human dopachrome tautomerase promoter by MITF, ER-α and chromatin remodelers during proliferation and senescence of human melanocytes'. Together they form a unique fingerprint.

Cite this