P4.33 ALTERNATIVELY SPLICED ISOFORMS OF DMP1 AND THEIR POTENTIAL ROLES IN HAIR GROWTH

Zhidong Yu, Steven W. Gordon, Allan J. Nixon, Janet E. Wildermoth and Allan J. Pearson

AgResearch Ruakura, Hamilton, New Zealand

Cyclin D interacting myb-like protein 1 alpha (DMP1- α) inhibits cell division in a pRb-independent manner and disruption of its expression facilitates cell transformation and tumorigenesis. We have previously reported the identification of a truncated DMP1 isoform present in anagen hair follicles.

Multiple novel cDNA sequences of DMP1 were isolated from keratinising epithelia of five mammalian species. Comparison with mice genomic DNA sequences shows that mouse DMP1- α, - β and γ are generated through selective use of the internal acceptor sites in exon 10. In sheep, multiple DMP1- α -like isoforms have also been identified. A much smaller DMP1-δ transcript was found only in ferrets, cats and dogs. The predicted amino acid sequences of the respective DMP1-α, -β, -γ and -δ isoforms are highly conserved among the species, suggesting similar roles. As all isoforms, other than DMP1- α lack some or all of the sequence required for the DNA binding and C-terminal transactivation domains, they may function as inhibitors of DMP1- α, as already demonstrated for hDMP1- β in human haematopoetic cells. The presence of multiple, potentially inhibitory isoforms in skin suggests that cellular functions of hDMP1- α are modulated by alternative DMP1 isoforms, possibly in an isoform-dependent or tissue-/cell-specific manner. As all isoforms share the sequence in the cyclin D binding region, competitive binding to D type cyclins may represent a mechanism for functional regulation. The cyclin D1 gene is also a direct target for transactivation by the Lef-1/ β-catenin pathway through a Lef-1 binding site in the cyclin D1 promoter.

DMP1- δ mRNA was expressed at much higher levels in the skin containing growing hair follicles, while the expression profiles of the other isoforms are low and relatively unchanged cross the ferret hair cycle. DMP1- δ mRNA was localised to the proximal keratogenous zone of the hair follicle cortex and terminally keratinising tongue filiform epithelial cells in all the three carnivore species. Hence, the up-regulation of DMP1-δ in carnivores could be associated with the terminal differentiation of keratinocytes in the hair follicles and tongue, but not in epidermal epithelial cells. The relationships between DMP1 isoforms and the Wnt signalling pathway in regulating terminal keratinocyte differentiation in the hair follicle is presently being investigated.