Contrasting roles of p57(KIP2) and p21(WAF1/CIP1/SDI1) transplanted human and bovine adrenocortical cells

Cell transplantation provides a way to compare the regulation of cell proli feration in the same cell type in cell culture and in a vascularized tissue structure in a host animal. The cyclin-dependent kinase inhibitors p57(KIP 2), p21(WAF1/CIP1/8DI1) and p27(KIP1) have been extensively studied in cell culture but their role in growth control in tissues is less well understoo d. In the present experiments we compared the behavior of cell cycle inhibi tors in human and bovine adrenocortical cells in culture and following cell transplantation in scid mice. p57 was expressed in the majority of cells i n the intact human adrenal cortex. However, double immunofluorescence showe d that cells that are in the cell cycle are p57(-) adrenocortical cells, p5 7 and p27 levels were not affected by inhibition of growth at high cell den sity, whereas p21 was higher in dividing than growth-inhibited cells. Howev er, p21 was also high in senescent adrenocortical cells. After transplantat ion of human adrenocortical cells in scid mice, p57 and p27 were observed i n most cells in the transplant tissue. Over time the number of p21(+) cells decreased greatly in human adrenocortical cells, but not in bovine adrenoc ortical cells. This difference correlated with lower levels of cell divisio n (assessed by Ki-67 or incorporation of bromodeoxyuridine) in the human ce lls in transplant tissues in comparison to bovine cells. The differences be tween human and bovine cells were observed both when cells were transplante d beneath the kidney capsule and when cells were injected subcutaneously in collagen gel, We conclude that the behavior of p57, but not p21, is consis tent with a role as a physiological mediator of proliferative quiescence in the adrenal cortex. The high level of p21 in dividing adrenocortical cells in culture, and in bovine adrenocortical cells in transplant tissues, may be a response to conflicting positive and negative growth influences. Cells may enter the cell cycle under the influence of a strong positive mitogeni c signal, but coexisting negative growth stimuli trigger a p21-dependent bl ock to further progression through the cell cycle. This model suggests that bovine adrenocortical cells respond to positive growth stimuli in transpla nt tissues but human cells lack this response. (C) 2001 Academic Press.