Expression and growth inhibitory effect of decapentaplegic Vg-related protein 6: evidence for a regulatory role in keratinocyte differentiation.

Decapentaplegic Vg-related protein 6 (DVR-6 or bone morphogenetic protein BMP-6) is a member of the DVR subgroup of the transforming growth factor beta superfamily, a large group of multifunctional signaling polypeptides that are expressed as secreted disulfide-bonded dimers proteolytically cleaved from larger precursors. The predominant expression of DVR-6 in the differentiating postmitotic layers of stratified squamous epithelia strongly suggests a role for DVR-6 in regulation of epithelial differentiation. In primary mouse keratinocytes induced to differentiate by suspension culture in methylcellulose, new expression of DVR-6 mRNA and protein was detected within 8 h among a majority of the suspended cells, which preceded the induction of expression of the suprabasal keratins K1 and K10. To test the hypothesis that DVR-6 is a keratinocyte growth regulatory factor, a retroviral expression vector expressing human DVR-6 was used to infect attached cultures of undifferentiated basal cells. Expression of DVR-6 in primary mouse keratinocytes before differentiation resulted in the secretion of prepro and processed (pro region) forms in the conditioned medium and a dramatic inhibition of cell growth. These findings suggest that inhibition of cell growth by DVR-6 may be a primary step in keratinocyte differentiation.