C-TERMINAL FRAGMENT OF PARATHYROID HORMONE-RELATED PROTEIN, PTHRP-(107-111), STIMULATES MEMBRANE-ASSOCIATED PROTEIN-KINASE-C ACTIVITY AND MODULATES THE PROLIFERATION OF HUMAN AND MURINE SKIN KERATINOCYTES

Low concentrations of the C-terminal parathyroid hormone-related prote in (PTHrP) fragments, PTHrP-(107-111) and PTHrP-(107-139), stimulated membrane-associated protein kinase Cs (PKCs), but not adenylyl cyclase or an internal Ca2+ surge, in early passage human skin keratinocytes and BALB/MK-2 murine skin keratinocytes. The fragment maximally stimul ated membrane-associated PKCs in BALB/MK-2 cells at 5 X 10(-9) to 10 M . The maximally PKC-stimulating concentrations of PTHrP-(107-111) also stopped or stimulated BALB/MK-2 keratinocyte proliferation depending on whether the cells were, respectively, cycling or quiescent at the t ime of exposure. Thus, just one brief (30-minute) pulse of 10(-8) M PT HrP-(107-111) stopped the proliferation of BALB/MK-2 keratinocytes for at least 5 days. On the other hand, daily 30-minute pulses of 10(-8) M PTHrP-(107-111) started and then maintained the proliferation of ini tially quiescent BALB/MK-2 cells. Similarly PTHrP-(107-111) inhibited DNA synthesis by cycling primary adult human keratinocytes, but it sti mulated DNA synthesis by quiescent human keratinocytes. (C) 1996, Gove rnment of Canada. Exclusive worldwide publication rights in the articl e have been transferred to Wiley-Liss Inc., in perpetuity.