Role of Cytoskeletal Diaphanous-Related Formins in Hearing Loss

Chiereghin, Chiara; Robusto, Michela; Massa, Valentina; Castorina, Pierangela; Ambrosetti, Umberto; Asselta, Rosanna; Soldà, Giulia

doi:10.3390/cells11111726

Cited by 8 publications

(5 citation statements)

References 75 publications

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“…Indeed, the hearing phenotype is inherited as a likely recessive trait in the family, and heterozygous carriers of the variant have normal hearing. This is in contrast with the mechanism of action of mutations in the other two diaphanous genes, DIAPH1 and DIAPH3 , which lead either to a gain-of-function effect or to the overexpression of the protein, respectively, and are transmitted as dominant alleles [ 4 , 10 , 12 ]. Despite the efforts to find a second NSHL family with potentially pathogenic variants in DIAPH2 , we still lack additional genetic data confirming the association of this gene with deafness.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, several genes encoding proteins involved in the structure and function of sensory hair cells are associated with NSHL, including cytoskeletal proteins. Among these, diaphanous -related formins (DRFs) are important regulators of actin nucleation and microtubule dynamics [ 3 , 4 ]. These multi-domain proteins are active as dimers and can be functionally divided into two parts.…”

Section: Introductionmentioning

confidence: 99%

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In-depth genetic and molecular characterization of diaphanous related formin 2 (DIAPH2) and its role in the inner ear

et al. 2023

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Diaphanous related formins are regulatory cytoskeletal protein involved in actin elongation and microtubule stabilization. In humans, defects in two of the three diaphanous genes (DIAPH1 and DIAPH3) have been associated with different types of hearing loss. Here, we investigate the role of the third member of the family, DIAPH2, in nonsyndromic hearing loss, prompted by the identification, by exome sequencing, of a predicted pathogenic missense variant in DIAPH2. This variant occurs at a conserved site and segregated with nonsyndromic X-linked hearing loss in an Italian family. Our immunohistochemical studies indicated that the mouse ortholog protein Diaph2 is expressed during development in the cochlea, specifically in the actin-rich stereocilia of the sensory outer hair cells. In-vitro studies showed a functional impairment of the mutant DIAPH2 protein upon RhoA-dependent activation. Finally, Diaph2 knock-out and knock-in mice were generated by CRISPR/Cas9 technology and auditory brainstem response measurements performed at 4, 8 and 14 weeks. However, no hearing impairment was detected. Our findings indicate that DIAPH2 may play a role in the inner ear; further studies are however needed to clarify the contribution of DIAPH2 to deafness.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In-depth genetic and molecular characterization of diaphanous related formin 2 (DIAPH2) and its role in the inner ear

et al. 2023

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“…Formins promote the initiation and elongation of actin filaments to participate in a variety of biological processes, such as cell signaling, organ development, microtubule stabilization, cell division, and endocytosis. [12][13][14][15] Forminmediated actin assembly is regulated by a protein family consisting of formin-binding proteins (FNBPs/FBPs). Previous studies showed that the high expression of FNBP1 is closely related to the highly aggressive characteristics of tumor cells within gastric and breast cancers.…”

Section: Introductionmentioning

confidence: 99%

FNBP4 is a Potential Biomarker Associated with Cuproptosis and Promotes Tumor Progression in Hepatocellular Carcinoma

Zheng¹,

Zhang²,

Wu³

et al. 2023

IJGM

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Background Hepatocellular carcinoma (HCC) is one of the most common malignant tumors that lacks an efficient therapeutic approach because of its elusive molecular mechanisms. This study aimed to investigate the biological function and potential mechanism of formin-binding protein 4 (FNBP4) in HCC. Methods FNBP4 expression in tissues and cells were detected by quantitative real-time PCR (qRT‒PCR), Western blot, and immunohistochemistry (IHC). The Kaplan-Meier method was used to explore the correlation between the FNBP4 expression and clinical survival. MTT, EdU incorporation, colony formation, and Transwell assays were performed to evaluate the function of FNBP4 in cell proliferation and migration in vitro. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was used to explore the potential mechanism of FNBP4. The prognostic risk signature and nomogram were constructed to demonstrate the prognostic value of FNBP4. Results We found that FNBP4 was upregulated in patients with HCC and associated with poor overall survival (OS). Furthermore, knockdown of FNBP4 inhibited the proliferation and migration in HCC cells. Then, we performed a KEGG pathway analysis of the coexpressed genes associated with FNBP4 and found that FNBP4 may be associated with tumor-related signaling pathways and cuproptosis. We verified that FNBP4 could cause cell cycle progression and inactivation of the hippo signaling pathway. A prognostic risk signature containing three FNBP4-related differentially expressed cuproptosis regulators (DECRs) was established and can be used as an independent risk factor to evaluate the prognosis of patients with HCC. In addition, a nomogram including a risk score and clinicopathological factors was used to predict patient survival probabilities. Conclusion FNBP4, as a potential biomarker associated with cuproptosis, promotes HCC cell proliferation and metastasis. We provide a new potential strategy for HCC treatment by targeting FNBP4.

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Section: Introductionmentioning

confidence: 99%

“…They also affect actin-dependent cell signaling and gene transcription, and genomic integrity [24,25]. Not surprisingly, germline and somatic mutations perturbing formins' activity and/or expression are associated with a growing number of pathological conditions, including developmental defects of the heart, nervous system, and kidney and aging-related diseases, inherited human diseases, and cancer [26,27]. However, the large number of formins and the seemingly functional redundancy among certain family members make it cumbersome to attribute a given cellular function to a specific formin by means of gene knockout or knockdown approaches.…”

Section: Introductionmentioning

confidence: 99%

Investigating Mammalian Formins with SMIFH2 Fifteen Years in: Novel Targets and Unexpected Biology

Innocenti

2023

IJMS

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The mammalian formin family comprises fifteen multi-domain proteins that regulate actin dynamics and microtubules in vitro and in cells. Evolutionarily conserved formin homology (FH) 1 and 2 domains allow formins to locally modulate the cell cytoskeleton. Formins are involved in several developmental and homeostatic processes, as well as human diseases. However, functional redundancy has long hampered studies of individual formins with genetic loss-of-function approaches and prevents the rapid inhibition of formin activities in cells. The discovery of small molecule inhibitor of formin homology 2 domains (SMIFH2) in 2009 was a disruptive change that provided a powerful chemical tool to explore formins’ functions across biological scales. Here, I critically discuss the characterization of SMIFH2 as a pan-formin inhibitor, as well as growing evidence of unexpected off-target effects. By collating the literature and information hidden in public repositories, outstanding controversies and fundamental open questions about the substrates and mechanism of action of SMIFH2 emerge. Whenever possible, I propose explanations for these discrepancies and roadmaps to address the paramount open questions. Furthermore, I suggest that SMIFH2 be reclassified as a multi-target inhibitor for its appealing activities on proteins involved in pathological formin-dependent processes. Notwithstanding all drawbacks and limitations, SMIFH2 will continue to prove useful in studying formins in health and disease in the years to come.

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Role of Cytoskeletal Diaphanous-Related Formins in Hearing Loss

Cited by 8 publications

References 75 publications

In-depth genetic and molecular characterization of diaphanous related formin 2 (DIAPH2) and its role in the inner ear

In-depth genetic and molecular characterization of diaphanous related formin 2 (DIAPH2) and its role in the inner ear

FNBP4 is a Potential Biomarker Associated with Cuproptosis and Promotes Tumor Progression in Hepatocellular Carcinoma

Investigating Mammalian Formins with SMIFH2 Fifteen Years in: Novel Targets and Unexpected Biology

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