Small Leucine Zipper Protein (sLZIP) Negatively Regulates Skeletal Muscle Differentiation via Interaction with α-Actinin-4

An, Hyoung Tae; Kim, Jeong‐Han; Yoo, Seung‐Min; Ko, Jesang

doi:10.1074/jbc.m113.515395

Cited by 13 publications

(12 citation statements)

References 34 publications

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“…We reason that because K255E is predominantly cytoplasmic (11), it is therefore unable to potentiate the activity of transcription factors in the nucleus. This is consistent with recent studies indicating that in response to myoblast differentiation signal, ACTN4 translocates into the nucleus and coactivates MEF2 transcription activity and myogenic gene expression (8). In contrast to hormone-dependent interaction between ACTN4 and nuclear receptors, this finding provides an alternative mechanism by which ACTN4 potentiates transcriptional activity.…”

Section: Actn4 Is a Transcriptional Coactivator Of Nf-bsupporting

confidence: 92%

“…This finding was recently confirmed by An et al (8). We also established that ACTN4 has a regulatory function on transcription mediated by nuclear hormone receptors such as estrogen receptor, retinoic acid receptor, peroxisome proliferator-activated receptor, and vitamin D receptor via its N-terminal nuclear receptor-interacting motif, LXXLL (9,10).…”

supporting

confidence: 80%

“…We and others have previously demonstrated that in addition to its role in the cytoplasm, ACTN4 is capable of potentiating the activity of several transcription factors that include nuclear receptors such as the estrogen receptor, peroxisome proliferator-activated receptors, retinoic acid receptor, vitamin D receptor (9 -11), and MEF2s (7,8). These observations raise a mechanistically important question regarding the role of ACTN4 in podocyte function and kidney disease.…”

Section: Discussionmentioning

confidence: 94%

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α-Actinin 4 Potentiates Nuclear Factor κ-Light-chain-enhancer of Activated B-cell (NF-κB) Activity in Podocytes Independent of Its Cytoplasmic Actin Binding Function

Zhao¹,

Hsu²,

Lim³

et al. 2015

Journal of Biological Chemistry

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Background: ACTN4 is an actin-binding protein and is associated with kidney diseases. Results: Nuclear ACTN4 interacts with NF-B and is recruited to NF-B-targeted promoters to potentiate its transcription activity. Conclusion: ACTN4 coactivates NF-B activity independently of its cytoplasmic activity in cultured human podocytes. Significance: Nuclear ACTN4 may play an important role in glomerular function.

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Section: Actn4 Is a Transcriptional Coactivator Of Nf-bsupporting

confidence: 92%

supporting

confidence: 80%

Section: Discussionmentioning

confidence: 94%

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α-Actinin 4 Potentiates Nuclear Factor κ-Light-chain-enhancer of Activated B-cell (NF-κB) Activity in Podocytes Independent of Its Cytoplasmic Actin Binding Function

Zhao¹,

Hsu²,

Lim³

et al. 2015

Journal of Biological Chemistry

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“…We have shown previously that ACTN4 potentiates transcriptional activation by MEF2 (25,26), NF-B (27,28), and NRs (29 -31). The newly identified nuclear function of ACTN4, its link to FSGS and MCD, and the beneficial effects of GCs on FSGS and MCD prompted us to investigate the role of ACTN4 in GC-mediated transcriptional regulation in podocytes and the effects of FSGS-linked ACTN4 mutations on GR transactivation activity.…”

mentioning

confidence: 85%

α Actinin 4 (ACTN4) Regulates Glucocorticoid Receptor-mediated Transactivation and Transrepression in Podocytes

Zhao

Khurana

Charkraborty

et al. 2017

Journal of Biological Chemistry

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Edited by Xiao-Fan WangGlucocorticoids are a general class of steroids that possess renoprotective activity in glomeruli through their interaction with the glucocorticoid receptor. However, the mechanisms by which glucocorticoids ameliorate proteinuria and glomerular disease are not well understood. In this study, we demonstrated that ␣ actinin 4 (ACTN4), an actin-cross-linking protein known to coordinate cytoskeletal organization, interacts with the glucocorticoid receptor (GR) in the nucleus of human podocytes (HPCs), a key cell type in the glomerulus critical for kidney filtration function. The GR-ACTN4 complex enhances glucocorticoid response element (GRE)-driven reporter activity. Stable knockdown of ACTN4 by shRNA in HPCs significantly reduces dexamethasone-mediated induction of GR target genes and GRE-driven reporter activity without disrupting dexamethasone-induced nuclear translocation of GR. Synonymous mutations or protein expression losses in ACTN4 are associated with kidney diseases, including focal segmental glomerulosclerosis, characterized by proteinuria and podocyte injury. We found that focal segmental glomerulosclerosis-linked ACTN4 mutants lose their ability to bind liganded GR and support GRE-mediated transcriptional activity. Mechanistically, GR and ACTN4 interact in the nucleus of HPCs. Furthermore, disruption of the LXXLL nuclear receptor-interacting motif present in ACTN4 results in reduced GR interaction and dexamethasone-mediated transactivation of a GRE reporter while still maintaining its actin-binding activity. In contrast, an ACTN4 isoform, ACTN4 (Iso), that loses its actin-binding domain is still capable of potentiating a GRE reporter. Dexamethasone induces the recruitment of ACTN4 and GR to putative GREs in dexamethasone-transactivated promoters, SERPINE1, ANGPLT4, CCL20, and SAA1 as well as the NF-B (p65) binding sites on GR-transrepressed promoters such as IL-1␤, IL-6, and IL-8. Taken together, our data establish ACTN4 as a transcriptional co-regulator that modulates both dexamethasone-transactivated and -transrepressed genes in podocytes.

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“…Most importantly, our motif analysis revealed transcription factors that have not yet been reported or identified previously in cancer cachexia. These factors are related to cell cycle and myogenesis (E2f3, Yy1, and Creb3) [62][63][64], unfolding protein response (Xbp1) [65], and muscle fiber metabolism (ESRRA) [66]. Also, we identified an increased expression of the myogenic regulatory factors Myf6 and Myog.…”

Section: Discussionmentioning

confidence: 76%

MicroRNA-mRNA Co-sequencing Identifies Transcriptional and Post-transcriptional Regulatory Networks Underlying Muscle Wasting in Cancer Cachexia

Fernández¹,

Ferreira²,

Vechetti³

et al. 2019

Preprint

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Cachexia is a complex metabolic syndrome characterized by loss of skeletal muscle, leading to a significant weight loss that impacts patient morbidity and mortality. Given the complexity of gene regulatory networks that control gene expression, our objective was to perform an integrative mRNA and miRNA profiling to identify genetic programs that capture essential mechanistic details that promote muscle atrophy in cancer cachexia. Here, we used RNA sequencing to analyze miRNAs and mRNAs expression profiles in tibialis anterior (TA) muscles of the Lewis lung carcinoma model of cancer cachexia. In addition, we compared these findings with RNA-Seq data from C2C12 myotubes treated in vitro with the cachectic factors tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ). Extracellular matrix (ECM) alterations were validated by picrosirius staining, western blot, and fractal dimension analyses. We found 1,008 mRNAs and 18 miRNAs differentially expressed in cachectic mice. This set of genes was associated with the ECM, proteolysis, and inflammatory response. Enrichment analysis of transcriptional factor binding sites revealed activation of the atrophy-related transcriptional factors: NF-κB, Stat3, AP-1, and FoxO. Furthermore, the integration of mRNA and miRNA expression profiles identified posttranscriptional regulation by miRNAs of genes involved in ECM organization, cell migration, transcription factors binding, ion transport, and FoxO signaling pathway. C2C12 myotubes treated with TNF-α and IFN-γ similarly down-regulate subsets of ECM genes, including collagens. Our integrative analysis of miRNA-mRNA co-profiles comprehensive characterized regulatory relationships of molecular pathways and revealed miRNAs targeting ECM-associated genes in cancer cachexia. We also confirmed in C2C12 myotubes that changes in ECM-associated genes are dependent on inflammatory signaling of the cytokines TNF-α and IFN-γ.

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Small Leucine Zipper Protein (sLZIP) Negatively Regulates Skeletal Muscle Differentiation via Interaction with α-Actinin-4

Cited by 13 publications

References 34 publications

α-Actinin 4 Potentiates Nuclear Factor κ-Light-chain-enhancer of Activated B-cell (NF-κB) Activity in Podocytes Independent of Its Cytoplasmic Actin Binding Function

α-Actinin 4 Potentiates Nuclear Factor κ-Light-chain-enhancer of Activated B-cell (NF-κB) Activity in Podocytes Independent of Its Cytoplasmic Actin Binding Function

α Actinin 4 (ACTN4) Regulates Glucocorticoid Receptor-mediated Transactivation and Transrepression in Podocytes

MicroRNA-mRNA Co-sequencing Identifies Transcriptional and Post-transcriptional Regulatory Networks Underlying Muscle Wasting in Cancer Cachexia

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