Growth inhibition of BALB/c mouse keratinocytes by TGF-beta 1 and CeReS-18 appears to act through distinct mechanisms

Abstract

Cell growth is controlled by the complex interactions of both positive and negative growth modulators. Studies were performed to directly compare the growth inhibitory properties of TGF-beta 1 and CeReS-18, a novel cell surface sialoglycopeptide growth inhibitor. Growth inhibition by CeReS-18 and that by TGF-beta 1 shared some similarities although significant differences were apparent. Similarities included a dose-responsive inhibition of BALB/c mouse keratinocyte (MK) cell proliferation that could be nontoxic and reversible. Both CeReS-18 and TGF-beta 1 could equally inhibit the stimulation of DNA synthesis induced by serum or keratinocyte growth factor in MK cells, and in both cases the inhibition was not due to decreased KGF binding to the target cell surface receptor. Inhibition of cell proliferation with CeReS-18, followed by an immediate reincubation with either CeReS-18 or TGF-beta 1, suggested that the sites of arrest mediated by both inhibitors were similar but not necessarily identical. However, recovery from CeReS-18-induced growth inhibition could be achieved by either removing the CeReS-18 or adding calcium directly to CeReS-18-inhibited MK cells, while recovery from TGF-beta 1-induced growth arrest could be reversed only by TGF-beta 1 removal. In addition, the sensitivity of MK cells to CeReS-18-induced cell cycle arrest could be altered by changing the extracellular calcium concentration, but sensitivity to TGF-beta 1 was unaffected by the calcium environment of the MK cells. While recovery from cell cycle arrest was rapid and complete with MK cell cultures inhibited with CeReS-18, removal of TGF-beta 1 led to a slower and incomplete recovery of cell cycling.