Hypoxia-induced and calpain-dependent cleavage of filamin A regulates the hypoxic response

Zheng, Xiaowei; Zhou, Alex-Xianghua; Rouhi, Pegah; Uramoto, Hidetaka; Borén, Jan; Cao, Yihai; Pereira, Teresa; Akyürek, Levent M.; Poellinger, Lorenz

doi:10.1073/pnas.1320815111

Cited by 56 publications

(71 citation statements)

References 38 publications

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“…Consistent with the stronger contractility of vSMCs expressing FLNA ΔECS , actin and actin‐associated proteins were enriched on the FLNA ΔECS IP (Fig EV4, yellow in Table EV3). More nuclear proteins were found associated with editable FLNA, suggesting a nuclear role of FLNA or of its C‐terminal fragment as previously reported (Zheng et al , ).…”

Section: Resultssupporting

confidence: 84%

RNA editing of Filamin A pre‐ mRNA regulates vascular contraction and diastolic blood pressure

et al. 2018

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Epitranscriptomic events such as adenosine‐to‐inosine (A‐to‐I) RNA editing by ADAR can recode mRNAs to translate novel proteins. Editing of the mRNA that encodes actin crosslinking protein Filamin A (FLNA) mediates a Q‐to‐R transition in the interactive C‐terminal region. While FLNA editing is conserved among vertebrates, its physiological function remains unclear. Here, we show that cardiovascular tissues in humans and mice show massive editing and that FLNA RNA is the most prominent substrate. Patient‐derived RNA‐Seq data demonstrate a significant drop in FLNA editing associated with cardiovascular diseases. Using mice with only impaired FLNA editing, we observed increased vascular contraction and diastolic hypertension accompanied by increased myosin light chain phosphorylation, arterial remodeling, and left ventricular wall thickening, which eventually causes cardiac remodeling and reduced systolic output. These results demonstrate a causal relationship between RNA editing and the development of cardiovascular disease indicating that a single epitranscriptomic RNA modification can maintain cardiovascular health.

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Section: Resultssupporting

confidence: 84%

RNA editing of Filamin A pre‐ mRNA regulates vascular contraction and diastolic blood pressure

et al. 2018

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“…In particular, it has been demonstrated that FLNA physically interacts with HIF-1a (Zhenga et al 2014), that regulates angiogenesis through upregulation of vascular endothelial growth factor (VEGF) (Uramoto et al 2010, Berardi et al 2011, Semenza 2012. Whereas VEGF-driven angiogenesis may play an important role in endocrine tumourigenesis and tumour progression (Hanahan et al 1996) and several in vitro studies suggested that SS analogues display potent antiangiogenic properties (Woltering et al 1991, Barrie et al 1993, Danesi & Del Tacca 1996, Kumar et al 2004, we showed that SST2 agonist reduced VEGF protein levels and release, but this inhibitory effect was totally abolished in the absence of FLNA.…”

Section: Discussionmentioning

confidence: 72%

Filamin-A is required to mediate SST2 effects in pancreatic neuroendocrine tumours

Vitali

Cambiaghi

Zerbi

et al. 2016

Endocrine-Related Cancer

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Somatostatin receptor type 2 (SST2) is the main pharmacological target of somatostatin (SS) analogues widely used in patients with pancreatic neuroendocrine tumours (P-NETs), this treatment being ineffective in a subset of patients. Since it has been demonstrated that Filamin A (FLNA) is involved in mediating GPCR expression, membrane anchoring and signalling, we investigated the role of this cytoskeleton protein in SST2 expression and signalling, angiogenesis, cell adhesion and cell migration in human P-NETs and in QGP1 cell line. We demonstrated that FLNA silencing was not able to affect SST2 expression in P-NET cells in basal conditions. Conversely, a significant reduction in SST2 expression (K43G21%, P!0.05 vs untreated cells) was observed in FLNA silenced QGP1 cells after long term SST2 activation with BIM23120. Moreover, the inhibitory effect of BIM23120 on cyclin D1 expression (K46G18%, P!0.05 vs untreated cells), P-ERK1/2 levels (K42G14%; P!0.05 vs untreated cells), cAMP accumulation (K24G3%, P!0.05 vs untreated cells), VEGF expression (K31G5%, P!0.01 vs untreated cells) and in vitro release (K40G24%, P!0.05 vs untreated cells) was completely lost after FLNA silencing. Interestingly, BIM23120 promoted cell adhesion (C86G45%, P!0.05 vs untreated cells) and inhibited cell migration (K24G2%, P!0.00001 vs untreated cells) in P-NETs cells and these effects were abolished in FLNA silenced cells. In conclusion, we demonstrated that FLNA plays a crucial role in SST2 expression and signalling, angiogenesis, cell adhesion and cell migration in P-NETs and in QGP1 cell line, suggesting a possible role of FLNA in determining the different responsiveness to SS analogues observed in P-NET patients.

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“…A recent study showed that FLNA interacts with HIF-1␣ to promote tumor growth and angiogenesis (36). However, TIF-90 interacts with the 90-kD isoform of FLNA to inhibit rRNA synthesis and cell proliferation in leukemia cells (19).…”

Section: Discussionmentioning

confidence: 99%

Cytoskeletal Filamin A Differentially Modulates RNA Polymerase III Gene Transcription in Transformed Cell Lines

Wang

Zhao

Wei

et al. 2016

Journal of Biological Chemistry

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Edited by Linda SpremulliCytoskeletal filamin A (FLNA) is an important protein involved in multiple cellular processes. Previous studies have shown that FLNA can promote or inhibit cancer growth and development; however, the mechanisms underlying these events are not fully understood. Here we show that, in both 293T and SaOS2 cells, knockdown of FLNA significantly enhanced transcription of RNA polymerase (pol) III-transcribed genes except for a subset of tRNA genes. In contrast, re-expression of FLNA in an FLNA-deficient melanoma cell line (A7) repressed transcription of all pol III-transcribed genes, suggesting that FLNA inhibits pol III transcription in a cell type-specific manner. Chromatin immunoprecipitation assays revealed that the repression of pol III gene transcription by FLNA correlates with the decreased occupancy of the RNA pol III transcription machinery at promoters. Immunofluorescence microscopy and coimmunoprecipitation assays revealed that FLNA can associate with the RNA pol III transcription machinery through its actin-binding domain within nuclei. Mechanistic analysis revealed that FLNA suppresses pol III gene transcription by confining the recruitment of the RNA pol III transcription machinery at the promoters of the genes that are sensitive to the alteration of FLNA expression. These findings not only extend the understanding of FLNA function in cells but also provide novel insights into the mechanism by which FLNA represses cell proliferation.Eukaryotic RNA polymerase (pol) 3 III mediates the synthesis of many non-coding RNAs that include tRNA, 5S rRNA, U6 RNA, 7SL RNA, and other small RNAs. These RNA products account for about 15% of total cellular transcripts and are involved in the regulation of protein biogenesis, RNA splicing, protein transportation, and protein-coding gene transcription (1-3). In cancer, aberrant expression of pol III products strongly correlates with the transformed state (4 -6). Abnormal high expression of pol III products in cancer is attributed to increased expression of pol III transcription factors, discharge of repression by tumor suppressors, and activation of oncogene expression (2).Cytoskeletal filamin A (FLNA) is a 280-kDa protein comprised of two N-terminal calponin homology domains and a long C-terminal rod-like domain. FLNA cross-links with F-actin through the calponin homology domains to maintain the stability of the cellular 3D network. In addition, FLNA acts as a scaffold that binds to over 90 diverse functional proteins to regulate numerous cellular processes (7-9), including cell adhesion, migration, proliferation, angiogenesis, cell signaling, DNA repair, and transcription (10 -18). It is well established that FLNA mutations cause several congenital diseases, including defects of the brain, heart, and skeleton (8). FLNA can play dual roles in cancer development; that is, FLNA can promote or inhibit cancer growth and development depending on particular circumstances (10). However, the mechanisms underlying these events are not fully understood.We sh...

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Hypoxia-induced and calpain-dependent cleavage of filamin A regulates the hypoxic response

Cited by 56 publications

References 38 publications

RNA editing of Filamin A pre‐ mRNA regulates vascular contraction and diastolic blood pressure

RNA editing of Filamin A pre‐ mRNA regulates vascular contraction and diastolic blood pressure

Filamin-A is required to mediate SST2 effects in pancreatic neuroendocrine tumours

Cytoskeletal Filamin A Differentially Modulates RNA Polymerase III Gene Transcription in Transformed Cell Lines

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