Binding of Carbonic Anhydrase IX to 45S RDNA Genes is Prevented by Exportin-1 in Hypoxic Cells

Overview

Journal Biomed Res Int

Publisher Wiley

Specialties Biomedical Engineering
Biotechnology
General Medicine

Date 2015 Mar 21

PMID 25793203

Citations 9

Authors

Emanuele Sasso

Monica Vitale

Francesca Monteleone

Francesca Ludovica Boffo

Margherita Santoriello

Daniela Sarnataro

Corrado Garbi

Mariangela Sabatella

Bianca Crifo

Luca Alfredo Paolella

Giuseppina Minopoli

Jean-Yves Winum

Nicola Zambrano

Affiliations

Soon will be listed here.

Abstract

Carbonic anhydrase IX (CA IX) is a surrogate marker of hypoxia, involved in survival and pH regulation in hypoxic cells. We have recently characterized its interactome, describing a set of proteins interacting with CA IX, mainly in hypoxic cells, including several members of the nucleocytoplasmic shuttling apparatuses. Accordingly, we described complex subcellular localization for this enzyme in human cells, as well as the redistribution of a carbonic anhydrase IX pool to nucleoli during hypoxia. Starting from this evidence, we analyzed the possible contribution of carbonic anhydrase IX to transcription of the 45 S rDNA genes, a process occurring in nucleoli. We highlighted the binding of carbonic anhydrase IX to nucleolar chromatin, which is regulated by oxygen levels. In fact, CA IX was found on 45 S rDNA gene promoters in normoxic cells and less represented on these sites, in hypoxic cells and in cells subjected to acetazolamide-induced acidosis. Both conditions were associated with increased representation of carbonic anhydrase IX/exportin-1 complexes in nucleoli. 45 S rRNA transcript levels were accordingly downrepresented. Inhibition of nuclear export by leptomycin B suggests a model in which exportin-1 acts as a decoy, in hypoxic cells, preventing carbonic anhydrase IX association with 45 S rDNA gene promoters.

Citing Articles

Pharmacological inhibition of carbonic anhydrases with a positively charged pyridinium sulfonamide phenocopies the neuroprotective effects of genetic ablation in a murine setting of oxygen/glucose deprivation followed by re-oxygenation and is....

Amiranda S, Succoio M, Anzilotti S, Cuomo O, Petrozziello T, Tedeschi V Heliyon. 2025; 11(4):e42457.

PMID: 40028587 PMC: 11868941. DOI: 10.1016/j.heliyon.2025.e42457.

The common H232 STING allele shows impaired activities in DNA sensing, susceptibility to viral infection, and in monocyte cell function, while the HAQ variant possesses wild-type properties.

Froechlich G, Finizio A, Napolano A, Amiranda S, De Chiara A, Pagano P Sci Rep. 2023; 13(1):19541.

PMID: 37945588 PMC: 10636114. DOI: 10.1038/s41598-023-46830-5.

Carbonic anhydrase IX subcellular localization in normoxic and hypoxic SH-SY5Y neuroblastoma cells is assisted by its C-terminal protein interaction domain.

Succoio M, Amiranda S, Sasso E, Marciano C, Finizio A, De Simone G Heliyon. 2023; 9(8):e18885.

PMID: 37600419 PMC: 10432983. DOI: 10.1016/j.heliyon.2023.e18885.

Generation of a Retargeted Oncolytic Virus Encoding Adenosine Deaminase for Tumor Adenosine Clearance.

Gentile C, Finizio A, Froechlich G, DAlise A, Cotugno G, Amiranda S Int J Mol Sci. 2021; 22(24).

PMID: 34948316 PMC: 8705735. DOI: 10.3390/ijms222413521.

Thyroid Hormone Enhances Angiogenesis and the Warburg Effect in Squamous Cell Carcinomas.

Miro C, Nappi A, Cicatiello A, Di Cicco E, Sagliocchi S, Murolo M Cancers (Basel). 2021; 13(11).

PMID: 34205977 PMC: 8199095. DOI: 10.3390/cancers13112743.

References

Benej M, Pastorekova S, Pastorek J . Carbonic anhydrase IX: regulation and role in cancer. Subcell Biochem. 2013; 75:199-219. DOI: 10.1007/978-94-007-7359-2_11. View

Quin J, Devlin J, Cameron D, Hannan K, Pearson R, Hannan R . Targeting the nucleolus for cancer intervention. Biochim Biophys Acta. 2014; 1842(6):802-16. DOI: 10.1016/j.bbadis.2013.12.009. View

Hamperl S, Wittner M, Babl V, Perez-Fernandez J, Tschochner H, Griesenbeck J . Chromatin states at ribosomal DNA loci. Biochim Biophys Acta. 2013; 1829(3-4):405-17. DOI: 10.1016/j.bbagrm.2012.12.007. View

Zatovicova M, Tarabkova K, Svastova E, Gibadulinova A, Mucha V, Jakubickova L . Monoclonal antibodies generated in carbonic anhydrase IX-deficient mice recognize different domains of tumour-associated hypoxia-induced carbonic anhydrase IX. J Immunol Methods. 2003; 282(1-2):117-34. DOI: 10.1016/j.jim.2003.08.011. View

Yuan J, Reed A, Chen F, Stewart Jr C . Statistical analysis of real-time PCR data. BMC Bioinformatics. 2006; 7:85. PMC: 1395339. DOI: 10.1186/1471-2105-7-85. View

Alterio V, Hilvo M, Di Fiore A, Supuran C, Pan P, Parkkila S . Crystal structure of the catalytic domain of the tumor-associated human carbonic anhydrase IX. Proc Natl Acad Sci U S A. 2009; 106(38):16233-8. PMC: 2752527. DOI: 10.1073/pnas.0908301106. View

Zatovicova M, Pastorekova S . Modulation of cell surface density of carbonic anhydrase IX by shedding of the ectodomain and endocytosis. Acta Virol. 2013; 57(2):257-64. DOI: 10.4149/av_2013_02_257. View

Turner J, Dawson J, Sullivan D . Nuclear export of proteins and drug resistance in cancer. Biochem Pharmacol. 2012; 83(8):1021-32. PMC: 4521586. DOI: 10.1016/j.bcp.2011.12.016. View

Supuran C . Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat Rev Drug Discov. 2008; 7(2):168-81. DOI: 10.1038/nrd2467. View

10.

Livak K, Schmittgen T . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2002; 25(4):402-8. DOI: 10.1006/meth.2001.1262. View

11.

Monteleone F, Rosa R, Vitale M, DAmbrosio C, Succoio M, Formisano L . Increased anaerobic metabolism is a distinctive signature in a colorectal cancer cellular model of resistance to antiepidermal growth factor receptor antibody. Proteomics. 2013; 13(5):866-77. DOI: 10.1002/pmic.201200303. View

12.

Buanne P, Renzone G, Monteleone F, Vitale M, Monti S, Sandomenico A . Characterization of carbonic anhydrase IX interactome reveals proteins assisting its nuclear localization in hypoxic cells. J Proteome Res. 2012; 12(1):282-92. DOI: 10.1021/pr300565w. View

13.

Fukuda M, Asano S, Nakamura T, Adachi M, Yoshida M, Yanagida M . CRM1 is responsible for intracellular transport mediated by the nuclear export signal. Nature. 1997; 390(6657):308-11. DOI: 10.1038/36894. View

14.

Mekhail K, Rivero-Lopez L, Khacho M, Lee S . Restriction of rRNA synthesis by VHL maintains energy equilibrium under hypoxia. Cell Cycle. 2006; 5(20):2401-13. DOI: 10.4161/cc.5.20.3387. View

15.

Ilardi G, Zambrano N, Merolla F, Siano M, Varricchio S, Vecchione M . Histopathological determinants of tumor resistance: a special look to the immunohistochemical expression of carbonic anhydrase IX in human cancers. Curr Med Chem. 2013; 21(14):1569-82. PMC: 3979091. DOI: 10.2174/09298673113209990227. View

16.

Hanahan D, Weinberg R . Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74. DOI: 10.1016/j.cell.2011.02.013. View

17.

Cuvier C, Jang A, Hill R . Exposure to hypoxia, glucose starvation and acidosis: effect on invasive capacity of murine tumor cells and correlation with cathepsin (L + B) secretion. Clin Exp Metastasis. 1997; 15(1):19-25. DOI: 10.1023/a:1018428105463. View

18.

Goodfellow S, Zomerdijk J . Basic mechanisms in RNA polymerase I transcription of the ribosomal RNA genes. Subcell Biochem. 2012; 61:211-36. PMC: 3855190. DOI: 10.1007/978-94-007-4525-4_10. View

19.

Dubois L, Peeters S, van Kuijk S, Yaromina A, Lieuwes N, Saraya R . Targeting carbonic anhydrase IX by nitroimidazole based sulfamides enhances the therapeutic effect of tumor irradiation: a new concept of dual targeting drugs. Radiother Oncol. 2013; 108(3):523-8. DOI: 10.1016/j.radonc.2013.06.018. View

20.

Sedlakova O, Svastova E, Takacova M, Kopacek J, Pastorek J, Pastorekova S . Carbonic anhydrase IX, a hypoxia-induced catalytic component of the pH regulating machinery in tumors. Front Physiol. 2014; 4:400. PMC: 3884196. DOI: 10.3389/fphys.2013.00400. View