bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2021–09–26
fiveteen papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne
  1. Incidental occurrence of papillary renal cell carcinoma in the native kidney with autosomal dominant polycystic kidney disease after renal transplantation: A case report.
  2. A Presumed Synonymous Mutation of PKD2 Caused Autosomal Dominant Polycystic Kidney Disease in a Chinese Family.
  3. NS398 as a potential drug for autosomal-dominant polycystic kidney disease: Analysis using bioinformatics, and zebrafish and mouse models.
  4. The Immunofluorescence-Based Detection of Hedgehog Pathway Components in Primary Cilia of Cultured Cells.
  5. Hypocitraturia is present when renal function is impaired in diverse nephropathies and is not related with serum bicarbonate levels.
  6. Novel zebrafish polycystic kidney disease (PKD) models reveal functions of the Hippo pathway in renal cystogenesis.
  7. Renal ROCK Activation and Its Pharmacological Inhibition in Patients With Diabetes.
  8. Primary Cilia Mediate TSH-Regulated Thyroglobulin Endocytic Pathways.
  9. Somatostatin analog therapy effectiveness on the progression of polycystic kidney and liver disease: A systematic review and meta-analysis of randomized clinical trials.
  10. ROCK1 Mediates Retinal Glial Cell Migration Promoted by Acrolein.
  11. Ttc30a affects tubulin modifications in a model for ciliary chondrodysplasia with polycystic kidney disease.
  12. LncRNA DLGAP1-AS1 accelerates glioblastoma cell proliferation through targeting miR-515-5p/ROCK1/NFE2L1 axis and activating Wnt signaling pathway.
  13. Characterization of Smoothened Phosphorylation and Activation.
  14. Calcium signal transmission by axonemal microtubules as an optimized information pathway in cilia and flagella.
  15. miR-497-5p induces apoptosis in K562 cells by downregulating ROCK1.
  1. Mol Clin Oncol. 2021 Nov;15(5): 223
    Incidental occurrence of papillary renal cell carcinoma in the native kidney with autosomal dominant polycystic kidney disease after renal transplantation: A case report.
    Mahmoud Abbas, Melanie Pätzel, Angelika Thurn, Olaf Anselm Brinkmann, Olaf Bettendorf.
      Autosomal dominant polycystic kidney disease (ADPKD) is one of the best-known genetic diseases. Almost half of the patients with ADPKD will develop end-stage renal disease, and the majority of patients are treated with renal transplantation. The current study presents a case that developed papillary renal cell carcinoma (PRCC) in the native right kidney 10 years after renal transplantation. PRCC is a not common malignant tumour entity (18.5% of all cases of renal cell carcinoma) compared with common clear cell renal carcinoma (65-70% of all cases of RCC).
    Keywords:  autosomal dominant polycystic kidney disease; incidental case; papillary renal cell carcinoma; renal transplantation
    DOI:  https://doi.org/10.3892/mco.2021.2386
  2. Curr Med Sci. 2021 Sep 20.
    A Presumed Synonymous Mutation of PKD2 Caused Autosomal Dominant Polycystic Kidney Disease in a Chinese Family.
    Lin-Xia Deng, Yuan Yang, Jing Yang, Luo-Wen Zhou, Kang Wang, Jian-Hua Zhou.
       OBJECTIVE: Autosomal dominant polycystic kidney disease (ADPKD) is mainly caused by the pathogenic mutation of PKD1 or PKD2 gene and usually affects bilateral kidneys. Synonymous mutations are generally assumed to be neutral as they do not alter amino acids. Herein, we described an extremely rare ADPKD child caused by a heterozygous synonymous mutation of PKD2 gene accompanied by massive proteinuria and congenital solitary kidney.
    METHODS: Clinical characteristics of the patients were summarized. Whole-exome sequencing was performed to screen the disease-causing gene mutation, and reverse transcription polymerase chain reaction (RT-PCR) and Sanger sequencing were applied to analyze the impact of the identified mutation on gene transcription and splicing.
    RESULTS: Polycystic changes were found in the solitary kidney of a girl initially presented with nephrotic-range proteinuria. Thereafter her mother and 2 other family members were diagnosed to be ADPKD. Whole-exome sequencing of the proband identified a heterozygous synonymous mutation (c.1716G>A, p.Lys572=) located in the splicing site of exon 7 in PKD2 gene, which was co-segregated with the PKD phenotype in the family. RT-PCR and direct sequencing of amplified products revealed that this heterozygous synonymous mutation led to exon7 skipping in PKD2 gene.
    CONCLUSION: We reported an extremely rare child case of ADPKD2 in combination with solitary kidney and nephrotic-range proteinuria, and firstly confirmed the pathogenicity of a heterozygous synonymous mutation (c.1716G>A) in PKD2 gene. The results indicate that synonymous mutations should not be excluded from disease-causing if they are located in splicing site of an exon.
    Keywords:  PKD2 gene; autosomal dominant polycystic kidney disease; child; splicing; synonymous mutation
    DOI:  https://doi.org/10.1007/s11596-021-2436-9
  3. J Cell Mol Med. 2021 Sep 22.
    NS398 as a potential drug for autosomal-dominant polycystic kidney disease: Analysis using bioinformatics, and zebrafish and mouse models.
    Sixiu Chen, Linxi Huang, Shoulian Zhou, Qingzhou Zhang, Mengna Ruan, Lili Fu, Bo Yang, Dechao Xu, Changlin Mei, Zhiguo Mao.
      Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by uncontrolled renal cyst formation, and few treatment options are available. There are many parallels between ADPKD and clear-cell renal cell carcinoma (ccRCC); however, few studies have addressed the mechanisms linking them. In this study, we aimed to investigate their convergences and divergences based on bioinformatics and explore the potential of compounds commonly used in cancer research to be repurposed for ADPKD. We analysed gene expression datasets of ADPKD and ccRCC to identify the common and disease-specific differentially expressed genes (DEGs). We then mapped them to the Connectivity Map database to identify small molecular compounds with therapeutic potential. A total of 117 significant DEGs were identified, and enrichment analyses results revealed that they are mainly enriched in arachidonic acid metabolism, p53 signalling pathway and metabolic pathways. In addition, 127 ccRCC-specific up-regulated genes were identified as related to the survival of patients with cancer. We focused on the compound NS398 as it targeted DEGs and found that it inhibited the proliferation of Pkd1-/- and 786-0 cells. Furthermore, its administration curbed cystogenesis in Pkd2 zebrafish and early-onset Pkd1-deficient mouse models. In conclusion, NS398 is a potential therapeutic agent for ADPKD.
    Keywords:  NS398; autosomal-dominant polycystic kidney disease; bioinformatics analysis; clear-cell renal cell carcinoma; cystogenesis
    DOI:  https://doi.org/10.1111/jcmm.16903
  4. Methods Mol Biol. 2022 ;2374 89-94
    The Immunofluorescence-Based Detection of Hedgehog Pathway Components in Primary Cilia of Cultured Cells.
    Shu Yang, Xiaoyan Zheng.
      The primary cilium is a microtubule-based organelle that projects from the surface of vertebrate cells. Defects in the biogenesis of or transport through primary cilia affect Hedgehog signaling, and many Hedgehog pathway components traffic through or accumulate in cilia. This protocol provides methods for immunofluorescence staining of cilia-accumulated Hh pathway components, such as Smoothened, in cultured NIH 3T3 cells.
    Keywords:  Cilia; Cultured cells; Hedgehog (Hh) signaling; Immunofluorescence; Smoothened (Smo)
    DOI:  https://doi.org/10.1007/978-1-0716-1701-4_8
  5. Int Urol Nephrol. 2021 Sep 21.
    Hypocitraturia is present when renal function is impaired in diverse nephropathies and is not related with serum bicarbonate levels.
    Francisco José Borrego Utiel, Isidoro Herrera Contreras, Enoc Merino García, Clara Moriana Domínguez, Esther Ocaña Pérez, Maria José García Cortés.
       BACKGROUND: In autosomal dominant polycystic kidney disease (ADPKD) it is frequently found a reduction in urinary citrate of unknown origin. It has been suggested that it could be a marker of acid retention in chronic kidney disease. Our aim was to compare urinary citrate in ADPKD with other nephropathies and to show its relation with serum bicarbonate.
    METHODS: We determined urinary citrate in patients with several nephropathies and varied renal function. We included 291 patients, 119 with glomerular diseases, 116 with ADPKD, 21 with other nephropathies, and 35 patients with normal renal function.
    RESULTS: Urinary citrate was higher in women and in patients with normal renal function. ADPKD patients showed similar values of urinary citrate to patients with glomerular diseases and with other nephropathies. We observed a progressive reduction in urinary citrate with renal impairment, in a comparable way among patients with ADPKD and glomerular diseases. We did not observe a relationship with serum bicarbonate. Serum uric acid levels were significantly higher in patients with glomerular diseases than in ADPKD patients, even after correction with the degree of renal function.
    CONCLUSIONS: Hypocitraturia is not specific of ADPKD but it is also present in all tested nephropathies and is related with renal impairment and not with serum bicarbonate. It could be interesting to study urinary citrate as a marker of renal function and as a prognostic factor.
    Keywords:  Autosomal dominant polycystic kidney disease; Chronic kidney disease; Citrate; Glomerular disease; Uric acid
    DOI:  https://doi.org/10.1007/s11255-021-02992-7
  6. Dis Model Mech. 2021 Sep 21. pii: dmm.049027. [Epub ahead of print]
    Novel zebrafish polycystic kidney disease (PKD) models reveal functions of the Hippo pathway in renal cystogenesis.
    Zhiqin Ren, Zhiwei Zhang, Tzu-Ming Liu, Wei Ge.
      Hippo signaling pathway is a kinase cascade which plays an important role in organ size control. As the main effectors of the Hippo pathway, transcription coactivators Yap1/Wwtr1 are regulated by the upstream kinase Stk3. Recent studies in mammals have implicated Hippo pathway in kidney development and kidney diseases. To further illustrate its roles in vertebrate kidney, we generated a series of zebrafish mutants targeting stk3, yap1 and wwtr1 genes. The stk3-/- mutant exhibited edema, formation of glomerular cysts and pronephric tubule dilation during larval stage. Interestingly, disruption of wwtr1 but not yap1 significantly alleviated the renal phenotypes of the stk3-/- mutant, and overexpression of Wwtr1 with CMV promoter also induced pronephric phenotypes during larval stage, similar to those of the stk3-/- mutant. Notably, adult fish with Wwtr1 overexpression developed phenotypes similar to those of human polycystic kidney disease (PKD). Overall, our studies revealed roles of Stk3 and Wwtr1 in renal cyst formation. Using pharmacological approach, we further demonstrated that Stk3-deficient zebrafish could serve as a PKD model for drug development.
    Keywords:  Hippo signaling pathway; Kidney development; Polycystic kidney disease (PKD); Renal cyst formation; Zebrafish model
    DOI:  https://doi.org/10.1242/dmm.049027
  7. Front Pharmacol. 2021 ;12 738121
    Renal ROCK Activation and Its Pharmacological Inhibition in Patients With Diabetes.
    Keiichiro Matoba, Kensuke Sekiguchi, Yosuke Nagai, Yusuke Takeda, Hiroshi Takahashi, Tamotsu Yokota, Kazunori Utsunomiya, Rimei Nishimura.
      Rho-associated coiled-coil-containing protein kinase (ROCK) is a serine/threonine kinase with essential roles in cytoskeletal functions. Substantial evidence implicates ROCK as a critical regulator in the inception and progression of diabetic nephropathy through a mechanism involving mesangial fibrosis, podocyte apoptosis, and endothelial inflammation. Despite these experimental observations, human data is lacking. Here we show that the phosphorylated form of myosin phosphatase targeting subunit 1 (MYPT1), a ROCK substrate, was increased in both the glomerular and tubulointerstitial areas in patients with histologically confirmed diabetic nephropathy. We also conducted a retrospective pilot analysis of data from patients with diabetes to assess the renoprotective effects of fasudil, an ATP-competitive ROCK inhibitor licensed in Japan for the prevention of vasospasm following subarachnoid hemorrhage. Fifteen subjects (male, n = 8; female, n = 7; age 65.7 ± 14.7 years; body height, 161.1 ± 12.6 cm; body weight, 57.6 ± 13.7 kg; body mass index, 22.4 ± 3.7 kg/m2) were enrolled to evaluate blood pressure and the renal outcome after fasudil treatment. Of note, proteinuria was significantly reduced at the end of the fasudil treatment without affecting the blood pressure or estimated glomerular filtration rate. Taken together, these findings suggest that the administration of fasudil could be associated with a better renal outcome by inhibiting the ROCK activity in patients with diabetes.
    Keywords:  Rho-kinase (ROCK); cell signaling; chronic kidney disease; diabetes; diabetic nephropathy; fasudil
    DOI:  https://doi.org/10.3389/fphar.2021.738121
  8. Front Endocrinol (Lausanne). 2021 ;12 700083
    Primary Cilia Mediate TSH-Regulated Thyroglobulin Endocytic Pathways.
    Junguee Lee, Hae Joung Sul, Kun-Ho Kim, Joon Young Chang, Minho Shong.
      Primary cilia are sensory organelles with a variety of receptors and channels on their membranes. Recently, primary cilia were proposed to be crucial sites for exocytosis and endocytosis of vesicles associated with endocytic control of various ciliary signaling pathways. Thyroglobulin (Tg) synthesis and Tg exocytosis/endocytosis are critical for the functions of thyroid follicular cells, where primary cilia are relatively well preserved. LRP2/megalin has been detected on the apical surface of absorptive epithelial cells, including thyrocytes. LRP2/megalin on thyrocytes serves as a Tg receptor and can mediate Tg endocytosis. In this study, we investigated the role of primary cilia in LRP2/megalin expression in thyroid gland stimulated with endogenous TSH using MMI-treated and Tg-Cre;Ift88flox/flox mice. LRP2/megalin expression in thyroid follicles was higher in MMI-treated mice than in untreated control mice. MMI-treated mice exhibited a significant increase in ciliogenesis in thyroid follicular cells relative to untreated controls. Furthermore, MMI-induced ciliogenesis accompanied increases in LRP2/megalin expression in thyroid follicular cells, in which LRP2/megalin was localized to the primary cilium. By contrast, in Tg-Cre;Ift88flox/flox mice, thyroid with defective primary cilia expressed markedly lower levels of LRP2/megalin. Serum Tg levels were elevated in MMI-treated mice and reduced in Tg-Cre;Ift88flox/flox mice. Taken together, these results indicate that defective ciliogenesis in murine thyroid follicular cells is associated with impaired LRP2/megalin expression and reduced serum Tg levels. Our results strongly suggest that primary cilia harbors LRP2/megalin, and are involved in TSH-mediated endocytosis of Tg in murine thyroid follicles.
    Keywords:  LRP2/megalin; ciliogenesis; primary cilium; thyroglobulin endocytosis; thyroid follicular cell
    DOI:  https://doi.org/10.3389/fendo.2021.700083
  9. PLoS One. 2021 ;16(9): e0257606
    Somatostatin analog therapy effectiveness on the progression of polycystic kidney and liver disease: A systematic review and meta-analysis of randomized clinical trials.
    Tatsuya Suwabe, Francisco J Barrera, Rene Rodriguez-Gutierrez, Yoshifumi Ubara, Marie C Hogan.
       BACKGROUND: Uncertainty underlies the effectiveness of somatostatin analogues for slowing the progression of polycystic kidney or liver disease.
    METHODS: Eligible studies included randomized controlled trials (RCTs) evaluating somatostatin analog as therapy for patients with polycystic kidney disease (PKD) or polycystic liver disease (PLD) compared to placebo or standard therapy. Two reviewers independently screened studies identified from databases (MEDLINE, EMBASE, Cochrane Database), clinical trial registries, and references from pertinent articles and clinical practice guidelines. Outcome measurements were changes in total liver volume (TLV), total kidney volume (TKV), and estimated glomerular filtration rate (eGFR).
    RESULTS: Of 264 nonduplicate studies screened, 10 RCTs met the inclusion criteria. The body of evidence provided estimates warranting moderate confidence. Meta-analysis of 7 RCTs including a total of 652 patients showed that somatostatin analogs are associated with a lower %TLV growth rate compared to control (mean difference, -6.37%; 95% CI -7.90 to -4.84, p<0.00001), and with a lower %TKV growth rate compared to control (mean difference, -3.66%; 95% CI -5.35 to -1.97, p<0.0001). However, it was not associated with a difference in eGFR decline (mean difference, -0.96 mL/min./1.73m2; 95% CI -2.38 to 0.46, p = 0.19).
    CONCLUSIONS: Current body of evidence suggests that somatostatin analogs therapy slows the increase rate of TLV and TKV in patients with PKD or PLD compared to control within a 3-year follow-up period. It does not seem to have an effect on the change in eGFR. Somatostatin analogs therapy can be a promising treatment for ADPKD or ADPLD, and we need to continue to research its effectiveness for ADPKD or ADPLD.
    DOI:  https://doi.org/10.1371/journal.pone.0257606
  10. Front Med (Lausanne). 2021 ;8 717602
    ROCK1 Mediates Retinal Glial Cell Migration Promoted by Acrolein.
    Kanae Fukutsu, Miyuki Murata, Kasumi Kikuchi, Shiho Yoshida, Kousuke Noda, Susumu Ishida.
      Objective: Acrolein is a highly reactive aldehyde that covalently binds to cellular macromolecules and subsequently modulates cellular function. Our previous study demonstrated that acrolein induces glial cell migration, a pathological hallmark of diabetic retinopathy; however, the detailed cellular mechanism remains unclear. The purpose of this study was to investigate the role of acrolein in retinal glial cell migration by focusing on rho-associated coiled-coil-containing protein kinases (ROCKs). Methods: Immunofluorescence staining for ROCK isoforms was performed using sections of fibrovascular tissue obtained from the eyes of patients with proliferative diabetic retinopathy (PDR). Rat retinal Müller glial cell line, TR-MUL5, was stimulated with acrolein and the levels of ROCK1 were evaluated using real-time PCR and western blotting. Phosphorylation of the myosin-binding subunit of myosin light chain phosphatase [myosin phosphatase target subunit 1, (MYPT1)] and myosin light chain 2 (MLC2) was assessed. The cell migration rate of TR-MUL5 cells exposed to acrolein and/or ripasudil, a non-selective ROCK inhibitor, was measured using the Oris cell migration assay. Results: ROCK isoforms, ROCK1 and ROCK2, were positively stained in the cytosol of glial cells in fibrovascular tissues. In TR-MUL5 cells, the mRNA expression level of Rock1, but not Rock2, was increased following acrolein stimulation. In line with the PCR data, western blotting showed increase in ROCK1 and cleaved ROCK1 protein in TR-MUL5 cells stimulated with acrolein. N-acetylcysteine (NAC) suppressed acrolein-associated Rock1 upregulation in TR-MUL5 cells. Acrolein augmented the phosphorylation of MYPT1 and MLC2 and increased the cell migration rate of TR-MUL5 cells, both of which were abrogated by ripasudil. Conclusions: Our study demonstrated that ROCK1 mediates the migration of retinal glial cells promoted by the unsaturated aldehyde acrolein.
    Keywords:  acrolein; cell migration; diabetic retinopathy; retinal glial cells; rho-associated coiled-coil-containing protein kinase 1
    DOI:  https://doi.org/10.3389/fmed.2021.717602
  11. Proc Natl Acad Sci U S A. 2021 09 28. pii: e2106770118. [Epub ahead of print]118(39):
    Ttc30a affects tubulin modifications in a model for ciliary chondrodysplasia with polycystic kidney disease.
    Maike Getwan, Anselm Hoppmann, Pascal Schlosser, Kelli Grand, Weiting Song, Rebecca Diehl, Sophie Schroda, Florian Heeg, Konstantin Deutsch, Friedhelm Hildebrandt, Ekkehart Lausch, Anna Köttgen, Soeren S Lienkamp.
      Skeletal ciliopathies (e.g., Jeune syndrome, short rib polydactyly syndrome, and Sensenbrenner syndrome) are frequently associated with nephronophthisis-like cystic kidney disease and other organ manifestations. Despite recent progress in genetic mapping of causative loci, a common molecular mechanism of cartilage defects and cystic kidneys has remained elusive. Targeting two ciliary chondrodysplasia loci (ift80 and ift172) by CRISPR/Cas9 mutagenesis, we established models for skeletal ciliopathies in Xenopus tropicalis Froglets exhibited severe limb deformities, polydactyly, and cystic kidneys, closely matching the phenotype of affected patients. A data mining-based in silico screen found ttc30a to be related to known skeletal ciliopathy genes. CRISPR/Cas9 targeting replicated limb malformations and renal cysts identical to the models of established disease genes. Loss of Ttc30a impaired embryonic renal excretion and ciliogenesis because of altered posttranslational tubulin acetylation, glycylation, and defective axoneme compartmentalization. Ttc30a/b transcripts are enriched in chondrocytes and osteocytes of single-cell RNA-sequenced embryonic mouse limbs. We identify TTC30A/B as an essential node in the network of ciliary chondrodysplasia and nephronophthisis-like disease proteins and suggest that tubulin modifications and cilia segmentation contribute to skeletal and renal ciliopathy manifestations of ciliopathies in a cell type-specific manner. These findings have implications for potential therapeutic strategies.
    Keywords:  Xenopus; chondrodysplasia; cilia; cystic kidney disease; tubulin modifications
    DOI:  https://doi.org/10.1073/pnas.2106770118
  12. Brain Behav. 2021 Sep 18. e2321
    LncRNA DLGAP1-AS1 accelerates glioblastoma cell proliferation through targeting miR-515-5p/ROCK1/NFE2L1 axis and activating Wnt signaling pathway.
    Zixuan Wang, Yipeng Han, Qifeng Li, Baocheng Wang, Jie Ma.
       INTRODUCTION: Glioblastoma (GBM), the primary malignant tumor in the central nervous system, features high aggressiveness and mortality. Long noncoding RNAs (lncRNAs) can exert the crucial function in regulating various human diseases, including GBM. However, the function and mechanism of lncRNA DLGAP1 antisense RNA 1 (DLGAP1-AS1) in GBM remain still unknown.
    METHODS: DLGAP1-AS1 expression in GBM cells was detected by RT-qPCR. Functional assays were conducted to determine GBM cell proliferation and apoptosis. RIP, RNA pull down, and luciferase reporter assay were applied for measuring the interplay of DLGAP1-AS1 with other RNAs.
    RESULTS: DLGAP1-AS1 was distinctly upregulated in GBM cells. DLGAP1-AS1 depletion inhibited cell proliferation, but induced apoptosis. MiR-515-5p could be sponged by DLGAP1-AS1 in GBM cells and to repress cell proliferation in GBM. Further, Rho-associated coiled-coil containing protein kinase 1 (ROCK1) and Nuclear factor erythroid-2 like 1 (NFE2L1) were confirmed as the target gene of miR-515-5p. Wnt signaling pathway could be activated by DLGAP1-AS1 via regulating ROCK1 and NFE2L1 expression. Rescue assays proved that overexpression of both ROCK1 and NFE2L1 could totally reverse the inhibitory effect of silencing DLGAP1-AS1 on GBM cell proliferation.
    CONCLUSION: LncRNA DLGAP1-AS1 accelerated cell proliferation in GBM via targeting miR-515-5p/ROCK1/NFE2L1 axis and activating Wnt signaling pathway.
    Keywords:  DLGAP1-AS1; NFE2L1; ROCK1; glioblastoma; miR-515-5p
    DOI:  https://doi.org/10.1002/brb3.2321
  13. Methods Mol Biol. 2022 ;2374 121-137
    Characterization of Smoothened Phosphorylation and Activation.
    Jianhang Jia, Yuhong Han, Yong Suk Cho, Jin Jiang.
      The GPCR-family protein Smoothened (Smo) is an obligatory signal transducer of the Hedgehog (Hh) signaling pathway. Binding of Hh to its receptor Patched (Ptc) alleviates Ptc-mediated inhibition of Smo, allowing Smo to activate the Cubitus interruptus (Ci)/Gli family of zinc finger transcription factors. The activation of Smo is an early and crucial event in Hh signal transduction. Studies have shown that Hh induces cell surface/ciliary accumulation and phosphorylation of Smo by multiple kinases, including protein kinase A (PKA), casein kinase 1 (CK1), casein kinase 2 (CK2), G protein-coupled receptor kinase 2 (Gprk2/GRK2), and atypical PKC (aPKC). Here, we describe the assays used to examine the phosphorylation and activity of Smo, including in vitro kinase assay, phospho-specific antibodies, luciferase reporter assay, cell surface accumulation, and ciliary localization assays. These assays provide powerful tools to study Smo phosphorylation and activation, leading to mechanistic insight into Smo regulation.
    Keywords:  CK1; CK2; GRK2; Hedgehog; PKA; Phosphorylation; Primary cilium; Smoothened; aPKC
    DOI:  https://doi.org/10.1007/978-1-0716-1701-4_11
  14. J Bioenerg Biomembr. 2021 Sep 18.
    Calcium signal transmission by axonemal microtubules as an optimized information pathway in cilia and flagella.
    M V Satarić, T Nemeš, B M Satarić.
      Calcium plays a key role in signal transduction in eukaryotic cells. Besides controlling local functions of cells calcium ions are responsible for the generation of global signals such as waves and spikes. Pulsatile increases of calcium concentrations are generally considered to have a much higher fidelity of information transfer than simple tonic changes, since they are much less prone to noisy fluctuations. In that respect, it was clearly revealed that Ca2+ has very crucial involvement in many signaling pathways in cilia and flagella. We earlier established a model in which axonemal microtubules exhibit the features of nonlinear polyelectrolitic electric transmissions lines for efficient transport of cations, primarily Ca2+. These microtubules guide accumulated "ionic clods" which serve as the pulsatile signals aimed to regulate pertaining motor proteins, dyneins and kinesis. We here consider such Ca2+ signals in axoneme in the context of Shannon's and Fisher's information theories. It appears that the fast drift of these "ionic clouds" represents the optimized calcium signaling for control of "flagellary beats" as well as intraflagellary transport of proteins essential for the construction, elongation and maintenance of eukaryotic cilia and flagella themselves.
    Keywords:  Axoneme; Ca2+signals; Calcium ions; Ionic cloud; Microtubule
    DOI:  https://doi.org/10.1007/s10863-021-09920-5
  15. Am J Transl Res. 2021 ;13(8): 9278-9284
    miR-497-5p induces apoptosis in K562 cells by downregulating ROCK1.
    Nafei Chen, Zhen Meng, Jiaojie Song, Lingfang Kong, Yehua Zhang, Suli Guo, Xiaokun Zhang, Xin Lu, Licai Jiang, Ran Chen, Zongjiu Jiao, Liyun Zhao.
       OBJECTIVE: To validate the role of miR-497-5p in apoptosis in K562 cells by targeting Rho-associated kinase isoform 1 (ROCK1).
    METHODS: From January, 2017 to February, 2019, 57 patients with chronic myeloid leukemia (CML) treated in our hospital were included in patient group, and 50 healthy individuals were recruited as control group. miR-497-5p level in peripheral blood was quantitated using qRT-PCR. After transfecting with miR-497-5p overexpression vector and ROCK1 inhibitor, K562 cells were monitored in terms of proliferation (CCK8 assay), migration and invasion (Transwell), and apoptosis (flow cytometry). Binding loci between miR-497-5p and ROCK1 were predicted, and the targeting relationship was confirmed (dual-luciferase reporter (DLR) assay).
    RESULTS: miR-497-5p was poorly expressed in CML (P < 0.05). Forced overexpression of miR-497-5p or inhibition of ROCK1 suppressed malignant processes (proliferation, proliferation, migration and invasion) in K562 cells and induced apoptosis (P < 0.05). DLR assay revealed a decreased luciferase activity after miR-497-5p binding to ROCK1 (P < 0.05).
    CONCLUSION: miR-497-5p induces apoptosis in K562 cells by downregulating ROCK1.
    Keywords:  K562 cells; ROCK1; apoptosis; invasion and migration; miR-497-5p
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