Retinoic acid regulates cell cycle progression and cell differentiation in human monocytic THP-1 cells

Abstract

All-trans-retinoic acid (RA), a natural metabolite of retinol, carries out most of the biological activities of vitamin A and is required for normal growth, cell differentiation, and immune functions. In the present studies, THP-1 human monocytes were used to investigate the mechanisms by which RA may regulate progression through the G1/S phase of the cell cycle. Physiological concentrations of all-trans-RA reduced the levels of cyclin E mRNA by 6 h and reduced cyclin E protein in a dose-and time-dependent manner. Similar reductions were observed for the retinoic acid receptor RAR and RXR proteins. Concomitantly, RA increased the level of the cyclin-dependent kinase inhibitor p27 (Kip-1). The levels of retinoblastoma mRNA and protein (pRb) were also increased, while the proportion of hyperphosphorylated (phosphoserine 807/811) pRb was markedly reduced. Overall, RA increased the functionality of pRb as an inhibitor of cell cycle progression. Furthermore, RA reduced the binding activity of the transcription factor E2F to its core DNA element. Retinoic acid-induced changes in cell cyclerelated proteins occurred in 4-6 h, including reduced cyclin E expression in bromodeoxyuridine (BrdU)-labeled cells, before the onset of cell differentiation as indicated by an increase in the percentage of G1 phase cells and a reduction in S phase cells at 24 h. The expression of CD11b, a cell surface marker of macrophage-like differentiation was increased by RA, as was phagocytic activity. The multiple effects of RA on cell cycle progression may help to explain its welldocumented ability to induce the differentiation of THP-1 cells, and thereby to enhance macrophage-like immune functions.

Vitamin A and immune function: Retinoic acid modulates population dynamics in antigen receptor and CD38-stimulated splenic B cells

“…It was reported that RA could induce human B cell arrest in the late G 1 phase of the cell cycle by repressing the expression of cyclin E and cyclin A (34), which may explain the reduction of B cell proliferative activity and CFSE dilution in the presence of RA. The results we and others have observed in B cells are also consistent with our previous observation in the monocytic cell line, THP-1, in which RA inhibited THP-1 cell proliferation by inducing cell cycle arrest and concurrently promoted the cell differentiation and functional maturation of the THP-1 monocytes to macrophagelike phagocytic cells (51).…”

Mechanism of asymmetric ovarian development in chick embryos

“…The deceleration of cell proliferation in the right cortex appears to be mediated by inhibition of cyclin D1 expression by RA. Consistent with our present observations, other labs have shown that RA inhibits cyclin D1, cyclin E1 and cyclin-dependent kinase 6 in cultured cell lines (Balasubramanian et al, 2004;Chen and Ross, 2004;Sah et al, 2002). In addition to downregulating these cell cycle accelerators, RA stimulates the expression of several cell cycle inhibitors, including cyclin-dependent kinase inhibitor, p27Kip1 and p21Cip1 (Balasubramanian et al, 2004;Buzzard et al, 2003;Chen and Ross, 2004;Guidoboni et al, 2005).…”

“…The synthesis and distribution of RA is controlled by the coordinated expression of genes encoding RAsynthesizing retinaldehyde dehydrogenases (RALDH1, RALDH2 and RALDH3) (Zhao et al, 1996;Niederreither et al, 1997;Swindell et al, 1999;Mic et al, 2000;Niederreither et al, 2002) and RA-metabolizing cytochrome P450 proteins (CYP26A1, CYP26B1 and CYP26C1) (Fujii et al, 1997;Swindell et al, 1999;MacLean et al, 2001;Tahayato et al, 2003;Reijntjes et al, 2004). Because RA is involved in cell growth and differentiation, cell-cycle accelerator and suppressor genes have been studied as potential RA targets (Chen and Ross, 2004;Dragnev et al, 2004;Guidoboni et al, 2005).…”

Retinoic acid promotes mouse splenic B cell surface IgG expression and maturation stimulated by CD40 and IL-4

“…It is also worthy of mention that the reduction in B-cell growth by RA was not due to induction of apoptosis (data not shown). Overall, the ability of RA to regulate cell cycle progression may play a role in inhibiting cell proliferation while promoting differentiation [28,55].…”