Abstract
BackgroundThe understanding of cutaneous pigmentation biology is relevant from the biologic and clinical point of view. The binding of α-melanocortin and its specific receptor, on the plasma membrane of melanin synthesising cells, plays a crucial role in melanins biosynthesis. Furthermore, loss of MC1R function is associated with an increased incidence of melanoma and non-melanoma skin cancer. The expression of the α-melanocortin receptor gene is highly controlled but, at the present, region responsible for tissue-specific activity of the gene promoter has not been identified.MethodsWe have cloned the genomic sequences upstream the human MC1R coding gene. A DNA fragment of 5 kilobases upstream the human MC1R encoding sequence was placed in front of a reporter gene and several deletion mutants of such fragment have been prepared. These constructs have been tested for the ability to drive the melanocyte-specific gene expression of the reporter gene using transfection experiments in melanocyte and non-melanocyte cell lines. From these experiments we identified a DNA fragment with the ability to drive the gene transcription in a tissue-specific way and we used this small DNA fragment in DNA-protein interaction assays.ResultsWe show that the 150 base pairs upstream the MC1R gene initiation codon are able to drive the melanocyte-specific gene transcription. Furthermore, we provide experimental evidences suggesting that on such minimal melanocyte-specific gene promoter can assemble tissue-specific complexes.ConclusionThe present results strongly imply that the transcriptional regulation of the melanocyte-specific MC1R gene requires an internal promoter located in the 150 base pairs upstream the initiation codon.
Highlights
The understanding of cutaneous pigmentation biology is relevant from the biologic and clinical point of view
The present results strongly imply that the transcriptional regulation of the melanocyte-specific MC1R gene requires an internal promoter located in the 150 base pairs upstream the initiation codon
The adenylate cyclase pathway induces the expression of the microphtalmia-associated transcription factor (MITF), a member of the basic helixloop-helix transcription factors that through binding to the E-box (CANNTG) on the gene promoters is involved in the transcriptional regulation of several melanocyte-specific genes such as tyrosinase, Tyrosinase Related Protein-1 (TRP-1) and TRP-2 [5]
Summary
The understanding of cutaneous pigmentation biology is relevant from the biologic and clinical point of view. The binding of α-melanocortin and its specific receptor, on the plasma membrane of melanin synthesising cells, plays a crucial role in melanins biosynthesis. Melanocytes and neuroblasts through melanogenesis and catecholamine synthesis are capable of transforming the same precursor L-tyrosine [1]. These two pathways are potentially cytotoxic and mutagenic due to the production of reactive oxygen species [2]. The adenylate cyclase pathway induces the expression of the microphtalmia-associated transcription factor (MITF), a member of the basic helixloop-helix (bHLH) transcription factors that through binding to the E-box (CANNTG) on the gene promoters is involved in the transcriptional regulation of several melanocyte-specific genes such as tyrosinase, Tyrosinase Related Protein-1 (TRP-1) and TRP-2 [5]. Fair skin is a well-known risk factor for skin cancer, most of the aforementioned studies conclude that increased skin cancer susceptibility due to MC1R variation cannot be explained solely on the basis of pigmentary phenotype making the effects of the MC1R variants on skin cancer risk unrelated [9]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call