MRTF-dependent cytoskeletal dynamics drive efficient cell cycle progression

TL;DR

MRTF-SRF signaling is essential for cell proliferation by regulating cytoskeletal dynamics and contractility during division.

Contribution

This study reveals that MRTF–SRF activity is required for efficient cell cycle progression through cytoskeletal regulation.

Findings

MRTF-null cells show reduced proliferation and elevated senescence markers.

Cytoskeletal interference mimics MRTF-null phenotypes, linking contractility to proliferation.

Re-expression of MRTF-A reverses the proliferative defects in MRTF-null cells.

Abstract

Serum response factor (SRF) and its cofactors, myocardin-related transcription factors A and B (MRTF-A and MRTF-B, respectively), regulate transcription of numerous cytoskeletal structural and regulatory genes, and most MRTF/SRF inactivation phenotypes reflect deficits in cytoskeletal dynamics. We show that MRTF–SRF activity is required for effective proliferation of both primary and immortalised fibroblast and epithelial cells. Cells lacking the MRTFs or SRF proliferate very slowly, express elevated levels of senescence-associated secretory phenotype (SASP) factors and senescence-associated β-galactosidase activity, and inhibit proliferation of co-cultured primary wild-type cells. They exhibit decreased levels of CDK1 and CKS2 proteins, and elevated levels of CDK inhibitors, usually p27 (also known as CDKN1B). These phenotypes, which can be fully reversed by re-expression of MRTF-A, are also seen in wild-type cells arrested by serum deprivation. Moreover, in wild-type cells direct interference with cytoskeletal dynamics through inhibition of Rho kinases (ROCKs) or myosin ATPase induces a similar proliferative defect to that seen in MRTF-null cells. MRTF-null cells exhibit multiple cytoskeletal defects and markedly reduced contractility. We propose that MRTF–SRF signalling will be required for cell proliferation in cell types and environments where physical progression through cell cycle transitions requires high contractility.

Highlighted Article:
MRTF-SRF activity is necessary for proliferation in cells where actin cytoskeletal remodelling and contractility is important during division.

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