Abstract
Small heterodimer partner (SHP) is an atypical member of nuclear receptor superfamily that lacks a DNA-binding domain. In previous study, we showed that SHP, c-jun, p65 of NF-gammaB subunits, and p21WAF1 expression was increased during monocytic differentiaton with the exposure of human leukemia cells to a differentiation agent, PMA. In this study, c-Jun and p65 were shown to mediate the transcriptional activation of the SHP promoter. In addition, SHP induced the cell cycle regulatory protein levels and cooperatively increased an induction of p21WAF1 expression with p65. Furthermore, SHP protected differentiated cells from etoposide-induced cellular apoptosis through the induction and cytoplasmic sequestration of p21WAF1. Complex formation between SHP and p21WAF1 was demonstrated by means of coimmunoprecipitation. These results suggest that SHP prolongs a cellular survival of differentiating monocytes through the transcriptional regulation of target genes of cell survival and differentiation.
Highlights
The molecular mechanisms regulating cell differentiation involve a fine and complex balance of proteins and signal transduction pathways that modulate the progression through control of cell cycle and cell survival (Scott et al, 1994; Cory, 1995)
To investigate the influence on the basal level of cellular proteins related to monocytic differentiation, U937 cells were stimulated with PMA and assayed with immunoblotting
The control of commitment is crucial for the timing of differentiation, whereas the control of subsequent gene expression is crucial for the determination of the particular differentiated phenotype
Summary
The molecular mechanisms regulating cell differentiation involve a fine and complex balance of proteins and signal transduction pathways that modulate the progression through control of cell cycle and cell survival (Scott et al, 1994; Cory, 1995). Little is known regarding the molecular mechanisms governing the monocyte differentiation to macrophage, promonocytic human cell lines, can be triggered to differentiate to human macrophages by defined stimuli (Oberg et al, 1993; Henkel et al, 1999). Agents such as phorbol esters (PMA) induce their exit from the cell cycle at G1, leading to their differentiation, which is characterized by the appearance of macrophage-like features such as cell surface integrins, adherence to plastic, and the production of reactive oxygen intermediates (Freytag, 1988; Baeuerle and Henkel, 1994; Casini and Pelicci, 1999). NF-κB plays a key role in cell differentiation by conferring cell survival that in the case of macrophages is
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