REGULATION OF THE 28 KDA HEAT-SHOCK PROTEIN BY RETINOIC ACID DURING DIFFERENTIATION OF HUMAN LEUKEMIC HL-60 CELLS

Dysregulation of hematopoietic cellular differentiation contributes to leukemogenesis. Unfortunately relatively little is known about how ce ll differentiation is regulated. Considering that heat shock proteins (hsp) and specifically the small hsps have been increasingly linked to growth regulation, we sought to determine whether the mammalian small hsp (hsp28) is a growth-regulatory candidate during hematopoietic cel l differentiation. Because of its effects on cell growth and different iation and its increasing clinical use as a differentiating agent, we examined the effect of retinoic acid (RA) on hsp28 during differentiat ion of the human leukemic HL-60 cell line. Although hsp28 was constitu tively expressed at low levels in untreated HL-60 cells, steady state hsp28 protein increased transiently, concomitant with the onset of G1 cell cycle arrest. Furthermore, hsp28 phosphorylation transiently incr eased within one hour following treatment with RA. Interestingly, in c ontrast to other differentiating agents the induction of hsp28 by RA w as post-transcriptionally mediated with hsp28 protein and mRNA being d iscordantly regulated. These observations underscore the complex regul ation of hsp28 by RA during granulocytic differentiation of human leuk emic cells and indicate hsp28 as an intermediary in the pathway throug h which retinoids exert their growth and differentiative effects.