Differentiation-associated miR-22 represses Max expression and inhibits cell cycle progression

Abstract

Differentiation agents such as 12- O-tetradecanoylphorbol-13-acetate (TPA) engage cell signaling pathways that activate downstream transcriptional programs necessary for cell differentiation. Recent evidence has indicated microRNAs (miRNAs) are an integral part of these transcriptional programs, which target key proteins and impact cell growth thereby facilitating changes required for differentiation. To further investigate the role of miRNAs in cell growth and differentiation, we focused on miR-22, a miRNA induced by TPA in the HL-60 leukemia cell line model of monocytic differentiation. TPA-induced miR-22 transcription was found to be downstream of the protein kinase c (PKC)–extracellular regulated kinase (ERK) signaling module, a pathway central to the growth and differentiation of many different cell types. Enforced miR-22 expression inhibited the growth of several different cancer cell lines, causing an accumulation of cells in the G1 phase of the cell cycle. The mechanism of miR-22’s inhibitory effects involves targeting of the obligate c-Myc binding partner Max. Enforced miR-22 expression presumably lowers Max levels available for Myc binding, which differentially influenced the transcription of downstream targets of the Myc–Max complex. Our study provides additional support for miRNAs targeting key cellular regulatory microcircuits such as those governed by the Myc–Max transcriptional complex as well as their being active participants in cell growth and differentiation.