EXPRESSION AND GROWTH-INHIBITORY EFFECT OF DECAPENTAPLEGIC VG-RELATEDPROTEIN-6 - EVIDENCE FOR A REGULATORY ROLE IN KERATINOCYTE DIFFERENTIATION

Decapentaplegic Vg-related protein 6 (DVR-6 or bone morphogenetic prot ein BMP-6) is a member of the DVR subgroup of the transforming growth factor beta superfamily, a large group of multifunctional signaling po lypeptides that are expressed as secreted disulfide-bonded dimers prot eolytically cleaved from larger precursors. The predominant expression of DVR-6 in the differentiating postmitotic layers of stratified squa mous epithelia strongly suggests a role for DVR-6 in regulation of epi thelial differentiation. In primary mouse keratinocytes induced to dif ferentiate by suspension culture in methylcellulose, new expression of DVR-6 mRNA and protein was detected within 8 h among a majority of th e suspended cells, which preceded the induction of expression of the s uprabasal 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 undiffe rentiated basal cells. Expression of DVR-6 in primary mouse keratinocy tes before differentiation resulted in the secretion of prepro and pro cessed (pro region) forms in the conditioned medium and a dramatic inh ibition of cell growth. These findings suggest that inhibition of cell growth by DVR-6 may be a primary step in keratinocyte differentiation .