Hairless and the polyamine putrescine form a negative regulatory loop in the epidermis.
Hairless (HR) is a nuclear protein with corepressor activity that is highly expressed in the skin and hair follicle. Mutations in Hairless lead to hair loss accompanied by the appearance of papules (atrichia with papular lesions), and similar phenotypes appear when the key polyamine enzymes ornithine decarboxylase (ODC) and spermidine/spermine N(1) -acetyltransferase (SSAT) are overexpressed. Both ODC and SSAT transgenic mice have elevated epidermal levels of putrescine, leading us to investigate the mechanistic link between putrescine and HR. We show here that HR and putrescine form a negative regulatory network, as epidermal ODC expression is elevated when HR is decreased and vice versa. We also show that the regulation of ODC by HR is dependent on the MYC superfamily of proteins, in particular MYC, MXI1 and MXD3. Furthermore, we found that elevated levels of putrescine lead to decreased HR expression, but that the SSAT-TG phenotype is distinct from that found when HR is mutated. Transcriptional microarray analysis of putrescine-treated primary human keratinocytes demonstrated differential regulation of genes involved in protein-protein interactions, nucleotide binding and transcription factor activity, suggesting that the putrescine-HR negative regulatory loop may have a large impact on epidermal homeostasis and hair follicle cycling.
Department of Dermatology, Columbia University, College of Physicians & Surgeons, New York, NY, USA.
Courtney T
CT
Luke
Alexandre
A
Casta
Hyunmi
H
Kim
Angela M
AM
Christiano
D016475:3T3 Cells; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D004817:Epidermis / Q000378:metabolism*; D005786:Gene Expression Regulation; D006197:Hair; D015603:Keratinocytes / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011073:Polyamines / Q000378:metabolism; D025941:Protein Interaction Mapping; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011700:Putrescine / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D011073:Polyamines; D016271:Proto-Oncogene Proteins c-myc; D011700:Putrescine; D012097:Repressor Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C490267:HR protein, human; C543450:MXD3 protein, human; C079440:MXI1 protein, human; C088661:hr protein, mouse
gene regulation; hair cycle; hairless; mouse models; polyamines