Serum response factor‐cofactor interactions and their implications in disease

Abstract

Serum response factor (SRF), a member of the Mcm1, Agamous, Deficiens, and SRF (MADS) box transcription factor, is widely expressed in all cell types and plays a crucial role in the physiological function and development of diseases. SRF regulates its downstream genes by binding to their CArG DNA box by interacting with various cofactors. However, the underlying mechanisms are not fully understood, therefore attracting increasing research attention due to the importance of this topic. This review's objective is to discuss the new progress in the studies of the molecular mechanisms involved in the activation of SRF and its impacts in physiological and pathological conditions. Notably, we summarized the recent studies on the interaction of SRF with its two main types of cofactors belonging to the myocardin families of transcription factors and the members of the ternary complex factors. The knowledge of these mechanisms will create new opportunities for understanding the dynamics of many traits and disease pathogenesis especially, cardiovascular diseases and cancer that could serve as targets for pharmacological control and treatment of these diseases.

Advances in Targeting Cancer-Associated Genes by Designed siRNA in Prostate Cancer

“…These results support that targeted delivery of two siRNAs could be a therapeutic strategy for the treatment of PCa [89]. Serum response factor (SRF) is known as a vital transcription factor and has a significant role in regulating expression of genes involved in cell growth and differentiation [90]. Research revealed that knockdown of both RelA (also known as nuclear factor NFκB p65 subunit) and SRF by specific siRNAs through a non-virally modified cyclodextrin vector causes significant reductions in the invasion potential of the highly metastatic PC-3 cells, partly due to the reduction of MMP-9 [91].…”

MRTF: Basic Biology and Role in Kidney Disease

“…It was then discovered that (1) RhoA-activating mediators, such as lysophosphatidic acid, can stimulate SRF-dependent transcription, and (2) the active forms of RhoA, Rac1 and Cdc42 are also potent inducers of this process [ 31 , 32 ]. Moreover, while SRF was known to associate with members of the ternary complex factor (TCF) family [ 33 ], and the TCF/SRF complex was shown to bind to gene promoters via neighboring cis-elements (TCE, and SRE, respectively), Rho family-induced activation of SRE was TCF-independent [ 31 , 34 , 35 ]. Importantly, actin polymerization per se was shown to drive SRF-dependent transcription [ 35 , 36 ].…”

The Genomic Response to TGF-β1 Dictates Failed Repair and Progression of Fibrotic Disease in the Obstructed Kidney

“…including the myocardin-related transcription factors (MRTF-A, MRTF-B) and the ternary complex factors (TCF) (Small, 2012;Gau and Roy, 2018;Onuh and Qiu, 2021). This pathway is likely to be particularly important in the TGF-β1-directed differentiation of interstitially-trafficked vascular pericytes into the pro-fibrotic, highly contractile and α-smooth muscle actinrich myofibroblast lineage.…”

“…This pathway is likely to be particularly important in the TGF-β1-directed differentiation of interstitially-trafficked vascular pericytes into the pro-fibrotic, highly contractile and α-smooth muscle actinrich myofibroblast lineage. Indeed, complex formation between SRF and MRTF vs. TCF dictates the particular subset of SRF target genes induced (Onuh and Qiu, 2021). Emergence of the myofibroblastic phenotype appears coupled to joint regulation by the TGF-β1 and MRTF-A/SRF signaling networks which cooperate to promote expression of a distinct set of contractile and profibrotic genes (Olson and Nordheim, 2010;Small, 2012;Velasquez et al, 2013;Gau and Roy, 2018;Werner et al, 2019).…”