Figure 5
A model for an EGR1-dependent actin-sensing node in (del)5 or 5q– myelodysplastic syndromes that propagates p53/PTEN. (a) Schematic of the EGR1 promoter, whose activity is regulated by at least five serum-response element (SRE) consensus sites. In turn, Egr1 protein can act as a transcriptional activator to enhance the promoter activity of the tumor suppressor PTEN. (b) By driving actin filament assembly and diminishing the cellular pools of G-actin, mammalian Diaphanous-related formin (mDia1) is a potent activator of serum response factor (SRF), which, in turn, induces the expression of Egr1. Egr1 can act as a transcriptional regulator, with target genes including TGF-β, p53 and PTEN, thereby regulating cell proliferation and survival signaling in response to stress. Coupled with α-catenin-mediated SRF activation, multiple 5q candidates feed into this actin-sensing node, potentially propagating p53/PTEN signaling through Egr1. Furthermore, through its association with the phosphoinositide 3-kinase (PI3K) pathway, the 5q candidate, RPS14, can also amplify the p53/PTEN signal. Exquisite control of this actin-sensing mechanism centered on 5q candidate tumor-suppressor genes would be critical to controlling the proliferation and proper migration of hematopoietic progenitors and stem cells.
