Regulation of cell proliferation: Late down‐regulation of c‐myb preceding myelo‐monocytic cell differentiation

Abstract

Expression of the c-myb nuclear oncogene during the cell proliferation and differentiation of HL-60 human promyelocytic leukemia cells was characterized and compared to the expression of c-fos, another nuclear oncogene with transcriptional regulatory activity. During progression through the cell cycle, the amount of c-myb protein increased. The increase was commensurate with total cell size, thus preserving the relative abundance of c-myb protein present at the onset of the cell cycle. In HL-60 cells, the induced metabolic cascade leading to terminal myeloid or monocytic differentiation segregates into two steps occurring over two division cycles. Expression of c-myb did not diverge from the control until late in this metabolic cascade when it declined prior to onset of terminal differentiation. This course of expression was similar for both the retinoic acid induced myeloid or the 1,25-dihydroxy vitamin D2 induced monocytic terminal differentiation of the cells. Bromodeoxyuridine, which induces proliferative arrest but not phenotypic differentiation of these cells, induced the same course of c-myb expression as the inducers of terminal differentiation. The same course of c-myb expression with growth arrest induced by these three different means is consistent with a potential proliferation regulatory role for c-myb in late but not early events leading to terminal differentiation. The dynamics of c-myb expression during this process were qualitatively, but not quantitatively, similar to the course of c-fos expression. Thus, taken with previous results, then amongst the nuclear oncogenes or tumor suppressor genes, c-myc, RB, c-fos, and c-myb, only c-myc and RB expression exhibit early regulation during induced HL-60 cell differentiation.

Activation of extracellular signal-regulated kinases (ERKs) defines the first phase of 1,25-dihydroxyvitamin D3-induced differentiation of HL60 cells

“…Perhaps the most relevant to our studies is the suggestion by Yen et al [1985Yen et al [ , 1992 that there is an``early'' segment of myeloid or monocytic differentiation during which the cells become primed for differentiation but do not express lineage-speci®c phenotype. The ERK activation described in the present studies serves to de®ne this early, proliferative phase, but it should be noted that CD14 surface marker which characterizes monocytic lineage [Ziegler-Heitbrock and Ulevitch, 1993;Zhang et al, 1994] is highly expressed during this phase (Tables I±IV), so lineage selection is already evident, and thus cannot be described as`p recommitment'' [Yen et al, 1987].…”

Peroxisome Proliferator-Activated Receptor Ligands Affect Growth-Related Gene Expression in Human Leukemic Cells

“…Expression of these genes is cell cycleregulated, and inhibition of their expression with antisense at ASPET Journals on May 9, 2018 jpet.aspetjournals.org oligonucleotides has been found to affect cell cycle progression, cell division, and/or differentiation (Raschella et al, 1992). Inhibition of c-myb expression by compounds inducing differentiation has been widely studied in leukemic cells (Kuehl et al, 1988) and c-myb down-regulation accompanied the cessation of growth and the onset of differentiation markers (Yen et al, 1992). Our results also indicate that PPAR ligands induce the monocytic differentiation of HL-60 cells, …”

1,25‐dihydroxy vitamin D3 and 12‐O‐tetradecanoyl phorbol‐13‐acetate synergistically induce monocytic cell differentiation: FOS and RB expression

“…U937 cells were treated or not with D3 plus TPA and repiicate cultures harvested a t the indicated times. The average amount of c-fos protein expression per cell was measured by flow cytometry as previously described (Yen et al, 1992b). Figure 6 shows the results for D3 plus TPA treated cells.…”

“…The induction of c-fos in U937 cells does not by itself precipitate differentiation (Mitchell et al, 1986). Furthermore, monocytic differentiation of another leukemic cell line, HL-60, does not require c-fos message up-regulation (Mitchell et al, 1986;Yen et al, 1992b). The existing data thus pose questions on the role of c-fos which further data on FOS protein levels might help clarify.…”