Serum response factor: master regulator of the actin cytoskeleton and contractile apparatus

Serum response factor (SRF) is a highly conserved and widely expressed, single copy transcription factor that theoretically binds up to 1,216 permutations of a 10-base pair cis element known as the CArG box. SRF-binding sites were defined initially in growth-related genes. Gene inactivation or knockdown studies in species ranging from unicellular eukaryotes to mice have consistently shown loss of SRF to be incompatible with life. However, rather than being critical for proliferation and growth, these genetic studies point to a crucial role for SRF in cellular migration and normal actin cytoskeleton and contractile biology. In fact, recent genomic studies reveal nearly half of the >200 SRF target genes encoding proteins with functions related to actin dynamics, lamellipodial/filopodial formation, integrin-cytoskeletal coupling, myofibrillogenesis, and muscle contraction. SRF has therefore emerged as a dispensable transcription factor for cellular growth but an absolutely essential orchestrator of actin cytoskeleton and contractile homeostasis. This review summarizes the recent genomic and genetic analyses of CArG-SRF that support its role as an ancient, master regulator of the actin cytoskeleton and contractile machinery.

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Interaction of Serum Response Factor (SRF) with the Elk-1 B Box Inhibits RhoA-Actin Signaling to SRF and Potentiates Transcriptional Activation by Elk-1

Molecular and Cellular Biology ◽

10.1128/mcb.22.20.7083-7092.2002 ◽

2002 ◽

Vol 22 (20) ◽

pp. 7083-7092 ◽

Cited By ~ 40

Author(s):

Kasumi Murai ◽

Richard Treisman

Keyword(s):

Binding Site ◽

Transcriptional Activation ◽

Rho Gtpases ◽

Target Genes ◽

Serum Response Factor ◽

Relative Sensitivity ◽

Actin Dynamics ◽

Physical Interaction ◽

Response Factor ◽

Serum Response

ABSTRACT Serum response factor (SRF) is a transcription factor which regulates many immediate-early genes. Rho GTPases regulate SRF activity through changes in actin dynamics, but some SRF target genes, such as c-fos, are insensitive to this pathway. At the c-fos promoter, SRF recruits members of the ternary complex factor (TCF) family of Ets domain proteins through interactions with the TCF B-box region. Analysis of c-fos promoter mutations demonstrates that the TCF and ATF/AP1 sites adjoining the SRF binding site inhibit activation of the promoter by RhoA-actin signaling. The presence of the TCF binding site is sufficient for inhibition, and experiments with an altered-specificity Elk-1 derivative demonstrate that inhibition can be mediated by the Elk-1 TCF. Using Elk-1 fusion proteins that can bind DNA autonomously, we show that inhibition of RhoA-actin signaling requires physical interaction between the Elk-1 B box and SRF. These results account for the insensitivity of c-fos to RhoA-actin signaling. Interaction of the B box with SRF also potentiates transcriptional activation by the Elk-1 C-terminal activation domain. Combinatorial interactions between SRF and TCF proteins are thus likely to play an important role in determining the relative sensitivity of SRF target genes to Ras- and Rho-controlled signal transduction pathways.

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Serum Response Factor Is Essential for Maintenance of Podocyte Structure and Function

Journal of the American Society of Nephrology ◽

10.1681/asn.2017050473 ◽

2017 ◽

Vol 29 (2) ◽

pp. 416-422 ◽

Cited By ~ 11

Author(s):

Bing Guo ◽

Qing Lyu ◽

Orazio J. Slivano ◽

Ronald Dirkx ◽

Christine K. Christie ◽

...

Keyword(s):

Transcription Factor ◽

Actin Cytoskeleton ◽

Serum Response Factor ◽

Mesangial Cells ◽

Vital Role ◽

Structure And Function ◽

Response Factor ◽

And Function ◽

Serum Response

Podocytes contain an intricate actin cytoskeleton that is essential for the specialized function of this cell type in renal filtration. Serum response factor (SRF) is a master transcription factor for the actin cytoskeleton, but the in vivo expression and function of SRF in podocytes are unknown. We found that SRF protein colocalizes with podocyte markers in human and mouse kidneys. Compared with littermate controls, mice in which the Srf gene was conditionally inactivated with NPHS2-Cre exhibited early postnatal proteinuria, hypoalbuminemia, and azotemia. Histologic changes in the mutant mice included glomerular capillary dilation and mild glomerulosclerosis, with reduced expression of multiple canonical podocyte markers. We also noted tubular dilation, cell proliferation, and protein casts as well as reactive changes in mesangial cells and interstitial inflammation. Ultrastructure analysis disclosed foot process effacement with loss of slit diaphragms. To ascertain the importance of SRF cofactors in podocyte function, we disabled the myocardin-related transcription factor A and B genes. Although loss of either SRF cofactor alone had no observable effect in the kidney, deficiency of both recapitulated the Srf-null phenotype. These results establish a vital role for SRF and two SRF cofactors in the maintenance of podocyte structure and function.

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Angiotensin II–Induced Stimulation of Smooth Muscle α-Actin Expression by Serum Response Factor and the Homeodomain Transcription Factor MHox

Circulation Research ◽

10.1161/01.res.81.4.600 ◽

1997 ◽

Vol 81 (4) ◽

pp. 600-610 ◽

Cited By ~ 72

Author(s):

Martina B. Hautmann ◽

Maria M. Thompson ◽

Ellen A. Swartz ◽

Eric N. Olson ◽

Gary K. Owens

Keyword(s):

Transcription Factor ◽

Smooth Muscle ◽

Angiotensin Ii ◽

Serum Response Factor ◽

Response Factor ◽

Homeodomain Transcription Factor ◽

Actin Expression ◽

Serum Response ◽

Stimulation Of

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Serum Response Factor (SRF)-cofilin-actin signaling axis modulates mitochondrial dynamics

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1208141109 ◽

2012 ◽

Vol 109 (38) ◽

pp. E2523-E2532 ◽

Cited By ~ 29

Author(s):

Henning Beck ◽

Kevin Flynn ◽

Katrin S. Lindenberg ◽

Heinz Schwarz ◽

Frank Bradke ◽

...

Keyword(s):

Mitochondrial Function ◽

Serum Response Factor ◽

Mitochondrial Dynamics ◽

Actin Dynamics ◽

Response Factor ◽

Signaling Axis ◽

Mitochondrial Number ◽

Mitochondrial Networks ◽

The Impact ◽

Serum Response

Aberrant mitochondrial function, morphology, and transport are main features of neurodegenerative diseases. To date, mitochondrial transport within neurons is thought to rely mainly on microtubules, whereas actin might mediate short-range movements and mitochondrial anchoring. Here, we analyzed the impact of actin on neuronal mitochondrial size and localization. F-actin enhanced mitochondrial size and mitochondrial number in neurites and growth cones. In contrast, raising G-actin resulted in mitochondrial fragmentation and decreased mitochondrial abundance. Cellular F-actin/G-actin levels also regulate serum response factor (SRF)-mediated gene regulation, suggesting a possible link between SRF and mitochondrial dynamics. Indeed, SRF-deficient neurons display neurodegenerative hallmarks of mitochondria, including disrupted morphology, fragmentation, and impaired mitochondrial motility, as well as ATP energy metabolism. Conversely, constitutively active SRF-VP16 induced formation of mitochondrial networks and rescued huntingtin (HTT)-impaired mitochondrial dynamics. Finally, SRF and actin dynamics are connected via the actin severing protein cofilin and its slingshot phosphatase to modulate neuronal mitochondrial dynamics. In summary, our data suggest that the SRF-cofilin-actin signaling axis modulates neuronal mitochondrial function.

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The Cytoskeleton-associated PDZ-LIM Protein, ALP, Acts on Serum Response Factor Activity to Regulate Muscle Differentiation

Molecular Biology of the Cell ◽

10.1091/mbc.e06-09-0815 ◽

2007 ◽

Vol 18 (5) ◽

pp. 1723-1733 ◽

Cited By ~ 19

Author(s):

Pascal Pomiès ◽

Mohammad Pashmforoush ◽

Cristina Vegezzi ◽

Kenneth R. Chien ◽

Charles Auffray ◽

...

Keyword(s):

Serum Response Factor ◽

Critical Role ◽

Muscle Differentiation ◽

Actin Dynamics ◽

Response Factor ◽

Cytoskeletal Regulation ◽

Expression Construct ◽

Filament Bundles ◽

Serum Response

In this report, an antisense RNA strategy has allowed us to show that disruption of ALP expression affects the expression of the muscle transcription factors myogenin and MyoD, resulting in the inhibition of muscle differentiation. Introduction of a MyoD expression construct into ALP-antisense cells is sufficient to restore the capacity of the cells to differentiate, illustrating that ALP function occurs upstream of MyoD. It is known that MyoD is under the control of serum response factor (SRF), a transcriptional regulator whose activity is modulated by actin dynamics. A dramatic reduction of actin filament bundles is observed in ALP-antisense cells and treatment of these cells with the actin-stabilizing drug jasplakinolide stimulates SRF activity and restores the capacity of the cells to differentiate. Furthermore, we show that modulation of ALP expression influences SRF activity, the level of its coactivator, MAL, and muscle differentiation. Collectively, these results suggest a critical role of ALP on muscle differentiation, likely via cytoskeletal regulation of SRF.

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