Filamins in cell signaling, transcription and organ development

Zhou, Alex-Xianghua; Hartwig, John H.; Akyürek, Levent M.

doi:10.1016/j.tcb.2009.12.001

Cited by 280 publications

(324 citation statements)

References 84 publications

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“…It is especially involved in cell adhesion, spreading and motility, as well as in signaling events (mediated by p21-activating kinase 1) regulating cytoskeletal assembly and cell shape (Vadlamudi et al, 2002). As in MMECs, FLNA is upregulated in human tumor cells (Zhou et al, 2010), while it not defined as oncogenic protein. FLNA intensely stains numerous neovessels in the BM of MM patients, and is abundantly distributed in MMEC cellular protrusions, like to what happens in invading and migrating prostate cancer cells (Bedolla et al, 2009).…”

Section: Angiogenic Proteins Of Mmecs S Berardi Et Almentioning

confidence: 99%

Four proteins governing overangiogenic endothelial cell phenotype in patients with multiple myeloma are plausible therapeutic targets

et al. 2011

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Bone marrow (BM) angiogenesis has an important role in the initiation and progression of multiple myeloma (MM). We looked at novel mechanisms of vessel formation in patients with MM through a comparative proteomic analysis between BM endothelial cells (ECs) of patients with active MM (MMECs) and ECs of patients with monoclonal gammopathy of undetermined significance (MGECs) and of subjects with benign anemia (normal ECs). Four proteins were found overexpressed in MMECs: filamin A, vimentin, a-crystallin B and 14-3-3f/d protein, not yet linked to overangiogenic phenotype. These proteins gave a typical distribution in the BM of MM patients and in MMECs versus MGECs, plausibly according to a different functional state. Their expression was enhanced by vascular endothelial growth factor, fibroblast growth factor 2, hepatocyte growth factor and MM plasma cell conditioned medium in step with enhancement of MMEC angiogenesis. Their silencing RNA knockdown affected critical MMEC angiogenesis-related functions, such as spreading, migration and tubular morphogenesis. A gradual stabilization of 14-3-3f/d protein was observed, with transition from normal ECs to MGECs and MMECs that may be a critical step for the angiogenic switch in MMECs and maintenance of the cell overangiogenic phenotype. These proteins were substantially impacted by anti-MM drugs, such as bortezomib, lenalidomide and panobinostat. Results suggest that these four proteins could be new targets for the antiangiogenic management of MM patients.

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Section: Angiogenic Proteins Of Mmecs S Berardi Et Almentioning

confidence: 99%

Four proteins governing overangiogenic endothelial cell phenotype in patients with multiple myeloma are plausible therapeutic targets

et al. 2011

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“…Filamins are actin-binding proteins which link the actin network to cellular membranes and transmembrane receptors [9]. The interactions with a plethora of proteins link filamins to different cellular processes, such as signalling, transcriptional regulation, migration, and tissue organization [10]. In vertebrates, filamin A, B, and C (FLNA, FLNB, FLNC) are known.…”

Section: Introductionmentioning

confidence: 99%

Organ-wide profiling in mouse reveals high editing levels of Filamin B mRNA in the musculoskeletal system

et al. 2018

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Adenosine to inosine RNA editing in protein-coding messenger RNAs (mRNAs) potentially leads to changes in the amino acid composition of the encoded proteins. The mRNAs encoding the ubiquitously expressed actin-crosslinking proteins Filamin A and Filamin B undergo RNA editing leading to a highly conserved glutamine to arginine exchange at the identical position in either protein. Here, by targeted amplicon sequencing we analysed the RNA editing of Filamin B across several mouse tissues during post-natal development. We find highest filamin B editing levels in skeletal muscles, cartilage and bones, tissues where Filamin B function seems most important. Through the analysis of Filamin B editing in mice deficient in either ADAR1 or 2, we identified ADAR2 as the enzyme responsible for Filamin B RNA editing. We show that in neuronal tissues Filamin B editing drops in spliced transcripts indicating regulated maturation of edited transcripts. We show further that the variability of Filamin B editing across several organs correlates with its mRNA expression.

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“…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)(8)(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).…”

mentioning

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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Filamins in cell signaling, transcription and organ development

Cited by 280 publications

References 84 publications

Four proteins governing overangiogenic endothelial cell phenotype in patients with multiple myeloma are plausible therapeutic targets

Four proteins governing overangiogenic endothelial cell phenotype in patients with multiple myeloma are plausible therapeutic targets

Organ-wide profiling in mouse reveals high editing levels of Filamin B mRNA in the musculoskeletal system

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

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