Oncogenic FGFR Fusions Produce Centrosome and Cilia Defects by Ectopic Signaling

Niţă, Alexandru; Abraham, Sara P.; Krejčı́, Pavel; Bosakova, Michaela Kunova

doi:10.3390/cells10061445

Cited by 7 publications

(8 citation statements)

References 357 publications

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“…30 Although there are no reports mentioned scoliosis and cilia abnormality at the same time, the same gene is reported to be related to scoliosis or cilia abnormality in some articles. [34][35][36][37][38][39][40] In our patient, DNAAF2 variant impaired cilia motility, leading to situs versus, and may be related to her scoliosis phenotype. In future, to explore the causes of scoliosis in patients with PCD will help to raise the public's attention to the spinal health, and carry out early intervention on spinal abnormality.…”

Section: Discussionmentioning

confidence: 65%

Identification of Two Novel DNAAF2 Variants in Two Consanguineous Families with Primary Ciliary Dyskinesia

Lu¹,

Yang²,

Cheng³

et al. 2021

PGPM

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Section: Discussionmentioning

confidence: 65%

Identification of Two Novel DNAAF2 Variants in Two Consanguineous Families with Primary Ciliary Dyskinesia

Lu¹,

Yang²,

Cheng³

et al. 2021

PGPM

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“…However, scoliosis is often overlooked in patients with PCD as anteroposterior and lateral radiographs of the spine are not a routine examination. Although there are few reports linking scoliosis to PCD, some genes have been reported to be associated with abnormal cilia beating and scoliosis in previous research (Fei et al, 2010;Makrythanasis et al, 2014;Baschal et al, 2015;Zhou et al, 2015;Lu et al, 2021;Nita et al, 2021). As an increasing number of PCD model organisms are observed with scoliosis, the spinal examination of the patient needs to be taken seriously.…”

Section: Discussionmentioning

confidence: 99%

Case Report: DNAAF4 Variants Cause Primary Ciliary Dyskinesia and Infertility in Two Han Chinese Families

Guo

Yang

et al. 2022

Front. Genet.

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Background: Primary ciliary dyskinesia (PCD) is a rare genetic disorder, predominantly autosomal recessive. The dynein axonemal assembly factor 4 (DNAAF4) is mainly involved in the preassembly of multisubunit dynein protein, which is fundamental to the proper functioning of cilia and flagella. There are few reports of PCD-related pathogenic variants of DNAAF4, and almost no DNAAF4-related articles focused on sperm phenotype. Moreover, the association between DNAAF4 and scoliosis has never been reported, to the best of our knowledge.Materials and Methods: We recruited two patients with a clinical diagnosis of PCD. One came from a consanguineous and another from a non-consanguineous family. Clinical data, laboratory test results, and imaging data were analyzed. Through whole exome sequencing, immunofluorescence, electron microscopy, high-speed video microscopy analysis, and hematoxylin–eosin (HE) staining, we identified the disease-associated variants and validated the pathogenicity.Results: Proband 1 (P1, F1: II-1), a 19-year-old man, comes from a non-consanguineous family-I, and proband 2 (P2, F2: II-1), a 37-year-old woman, comes from a consanguineous family-II. Both had sinusitis, bronchiectasis, situs inversus, and scoliosis. P1 also had asthenoteratozoospermia, and P2 had an immature uterus. Two homozygous pathogenic variants in DNAAF4 (NM_130810.4), c.988C > T, p.(Arg330Trp), and DNAAF4 (NM_130810.4), c.733 C > T, p.(Arg245*), were identified through whole exome sequencing. High-speed microscopy analysis showed that most of the cilia were static in P1, with complete static of the respiratory cilia in P2. Immunofluorescence showed that the outer dynein arms (ODA) and inner dynein arms (IDA) were absent in the respiratory cilia of both probands, as well as in the sperm flagellum of P1. Transmission electron microscopy revealed the absence of ODA and IDA of respiratory cilia of P2, and HE staining showed irregular, short, absent, coiled, and bent flagella.Conclusion: Our study identified a novel variant c.733C > T, which expanded the spectrum of DNAAF4 variants. Furthermore, we linked DNAAF4 to asthenoteratozoospermia and likely scoliosis in patients with PCD. This study will contribute to a better understanding of PCD.

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“…FGFRs play a variety of roles in normal physiological and developmental processes, such as embryonic organ development, tissue repair, angiogenesis, and metabolism [17,18]. Substantial evidence suggests that abnormal FGFR activation is involved in the pathogenesis of cancer [19][20][21]. FGFR2 is considered to be a susceptibility gene for breast cancer, FGFR4 is a driving factor for breast cancer, and FGFR1 overexpression is found in nearly 50% of breast cancer patients.…”

Section: Plos Onementioning

confidence: 99%

Caffeic acid phenethyl ester suppresses metastasis of breast cancer cells by inactivating FGFR1 via MD2

Fang¹,

Xin²,

Chen³

et al. 2023

PLoS ONE

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Background Tumor metastasis is the main cause of death for breast cancer patients. Caffeic acid phenethyl ester (CAPE) has strong anti-tumor effects with very low toxicity and may be a potential candidate drug. However, the anti-metastatic effect and molecular mechanism of CAPE on breast cancer need more research. Methods MCF-7 and MDA-MB-231 breast cancer cells were used here. Wound healing and Transwell assay were used for migration and invasion detection. Western blot and RT-qPCR were carried out for the epithelial-to-myofibroblast transformation (EMT) process investigation. Western blot and immunofluorescence were performed for fibroblast growth factor receptor1 (FGFR1) phosphorylation and nuclear transfer detection. Co-immunoprecipitation was used for the FGFR1/myeloid differentiation protein2 (MD2) complex investigation. Results Our results suggested that CAPE blocks the migration, invasion, and EMT process of breast cancer cells. Mechanistically, CAPE inhibits FGFR1 phosphorylation and nuclear transfer while overexpression of FGFR1 reduces the anti-metastasis effect of CAPE. Further, we found that FGFR1 is bound to MD2, and silencing MD2 inhibits FGFR1 phosphorylation and nuclear transfer as well as cell migration and invasion. Conclusion This study illustrated that CAPE restrained FGFR1 activation and nuclear transfer through MD2/FGFR1 complex inhibition and showed good inhibitory effects on the metastasis of breast cancer cells.

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Oncogenic FGFR Fusions Produce Centrosome and Cilia Defects by Ectopic Signaling

Cited by 7 publications

References 357 publications

Identification of Two Novel DNAAF2 Variants in Two Consanguineous Families with Primary Ciliary Dyskinesia

Identification of Two Novel DNAAF2 Variants in Two Consanguineous Families with Primary Ciliary Dyskinesia

Case Report: DNAAF4 Variants Cause Primary Ciliary Dyskinesia and Infertility in Two Han Chinese Families

Caffeic acid phenethyl ester suppresses metastasis of breast cancer cells by inactivating FGFR1 via MD2

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