Figure 7
Model of MPA-induced miR-16 downregulation and cell-cycle control. In the absence of progestin stimulation, steady state levels of miR-16 repress the translation of key mRNAs required for cell-cycle progression, such as cyclin D1 and cyclin E mRNAs (left panel). Binding of progestins to PR (right panel) induces Stat3 activation via the activation of c-Src and Jak kinases (Step 1) [18]. At the same time, progestin-activated PR translocates to the nucleus where it binds to PREs, such as the c-Myc PRE (Step 2) [69]. In addition, Stat3 migrates to the nucleus and binds to its response elements (GAS sites) and is also known to act as a PR co-activator (Step 3) [71]. The latter event results in the upregulation of the oncogenic transcription factor c-Myc (Step 4), which represses miR-16 expression by binding to E-box response elements and inducing chromatin remodeling (decrease of AcH4 and increase of H3K9me3, Step 5) [36, 73, 74]. Decreased levels of miR-16 would result in an increased expression of its targets, including cyclin D1 and cyclin E, and would lead to cell growth (Step 6). PR, progesterone receptor; PREs, progesterone response elements.