Actin-dependent activation of serum response factor in T cells by the viral oncoprotein tip

Abstract

Serum response factor (SRF) acts as a multifunctional transcription factor regulated by mutually exclusive interactions with ternary complex factors (TCFs) or myocardin-related transcription factors (MRTFs). Binding of Rho- and actin-regulated MRTF:SRF complexes to target gene promoters requires an SRF-binding site only, whereas MAPK-regulated TCF:SRF complexes in addition rely on flanking sequences present in the serum response element (SRE). Here, we report on the activation of an SRE luciferase reporter by Tip, the viral oncoprotein essentially contributing to human T-cell transformation by Herpesvirus saimiri. SRE activation in Tip-expressing Jurkat T cells could not be attributed to triggering of the MAPK pathway. Therefore, we further analyzed the contribution of MRTF complexes. Indeed, Tip also activated a reporter construct responsive to MRTF:SRF. Activation of this reporter was abrogated by overexpression of a dominant negative mutant of the MRTF-family member MAL. Moreover, enrichment of monomeric actin suppressed the Tip-induced reporter activity. Further upstream, the Rho-family GTPase Rac, was found to be required for MRTF:SRF reporter activation by Tip. Initiation of this pathway was strictly dependent on Tip's ability to interact with Lck and on the activity of this Src-family kinase. Independent of Tip, T-cell stimulation orchestrates Src-family kinase, MAPK and actin pathways to induce SRF. These findings establish actin-regulated transcription in human T cells and suggest its role in viral oncogenesis.

Dasatinib inhibits TGFβ-induced myofibroblast differentiation through Src-SRF Pathway

“…Interestingly, we found that targeting Src using dasatinib was associated with decreased SRF which suggests that Src may transcriptionally regulates αSMA synthesis. In light of this finding, a study conducted in T-cells demonstrated that Src activation is necessary for the induction of SRF and transcriptional regulation of target genes (Katsch et al, 2012). Further studies are necessary to examine the Src-mediated transcriptional regulation in myofibroblasts.…”

EZH2 regulates neuroepithelium structure and neuroblast proliferation by repressing p21

“…Data represent the percentage of n = 51 sections (from three to four embryos). ( e ) HH11–12 embryos were electroporated in ovo with shCtrl or shEZH2 together with pSRE-luc plasmid [ 24 – 26 ] and β-gal reporter used as internal control; 48 h PE the neural tubes were dissected out, the tissue was disaggregated and the luciferase activity measured using the Life Technologies dual kit. Data represent mean of three experiments from five to seven embryos.…”

Actin dynamics in host–pathogen interaction

“…Although these aspects of actin dynamics are incompletely understood and notoriously difficult to visualize, even less is known about usurpation of them by virions. Nevertheless, several indications for the participation of these cellular processes in virion production/assembly have emerged .…”