Alternative titles; symbols
HGNC Approved Gene Symbol: CA9
Cytogenetic location: 9p13.3 Genomic coordinates (GRCh38): 9:35,673,928-35,681,159 (from NCBI)
The human MN antigen was originally identified in HeLa cells, where its expression was correlated with cell density. Pastorek et al. (1994) used a monoclonal antibody against MN to clone the human cDNA from a HeLa cell library. The polypeptide encoded by the cDNA has 4 distinct domains: a secretory signal sequence, an N-terminal helix-loop-helix (HLH) domain, a carbonic anhydrase (CA) domain, and a single transmembrane domain. The sequence also contains a putative nuclear localization signal and a putative N-linked glycosylation site. Northern blot analysis demonstrated that the gene is expressed as an mRNA of 1.5 kb. In vitro assays revealed that expressed MN protein binds zinc, has weak CA activity, has affinity for DNA, and transforms NIH 3T3 cells. Pastorek et al. (1994) noted that the domain between the CA and HLH domains resembles the activation region of some transcription factors. Furthermore, they confirmed earlier work that showed that MN is expressed in some carcinomas while being absent from the corresponding normal tissue. The authors speculated that MN may be involved in cell proliferation and transformation.
Hewett-Emmett and Tashian (1996) stated that MN is an alpha-carbonic anhydrase isoenzyme and suggested the designation carbonic anhydrase IX. Alpha-carbonic anhydrase isoenzymes show extensive diversity in tissue distribution and in their putative or established biologic functions.
Opavsky et al. (1996) noted that the region of the MN/CA protein between the signal peptide and the CA domain resembles a keratin sulfate attachment domain, suggesting that MN/CA9 may be a proteoglycan.
Carbonic anhydrases (CAs) are a family of zinc metalloenzymes. For background information on the CA family, see 114800.
Opavsky et al. (1996) cloned the genomic MN/CA9 region. The gene is encoded by 11 exons spanning 10.9 kb. The organization of exons and their relationship to the predicted protein domains suggest that the gene arose by exon shuffling. Discrepancies between the genomic sequence and the cDNA sequence published by Pastorek et al. (1994) led Opavsky et al. (1996) to determine a revised cDNA sequence (GenBank X66839). Southern blot analysis showed that MN/CA9 is a single-copy gene. The 5-prime untranslated region contains no TATA box, but has consensus sequences for transcription factors AP1 (JUN; 165160), AP2 (107580), and p53 (191170), as well as 2 consensus initiator (Inr) element motifs.
By fluorescence in situ hybridization, Ivanov et al. (1998) mapped the CA9 gene to 17q21.2. However, by radiation hybrid mapping, Nakagawa et al. (1998) assigned the MN/CA9 gene to 9p13-p12.
Hewett-Emmett, D., Tashian, R. E. Functional diversity, conservation, and convergence in the evolution of the alpha-, beta- and gamma- carbonic anhydrase gene families. Molec. Phylogenet. Evol. 5: 50-77, 1996. [PubMed: 8673298] [Full Text: https://doi.org/10.1006/mpev.1996.0006]
Ivanov, S. V., Kuzmin, I., Wei, M.-H., Pack, S., Geil, L., Johnson, B. E., Stanbridge, E. J., Lerman, M. I. Down-regulation of transmembrane carbonic anhydrases in renal cell carcinoma cell lines by wild-type von Hippel-Lindau transgenes. Proc. Nat. Acad. Sci. 95: 12596-12601, 1998. [PubMed: 9770531] [Full Text: https://doi.org/10.1073/pnas.95.21.12596]
Nakagawa, Y., Uemura, H., Hirao, Y., Yoshida, K., Saga, S., Yoshikawa, K. Radiation hybrid mapping of the human MN/CA9 locus to chromosome band 9p12-p13. Genomics 53: 118-119, 1998. [PubMed: 9787087] [Full Text: https://doi.org/10.1006/geno.1998.5483]
Opavsky, R., Pastorekova, S., Zelnik, V., Gibadulinova, A., Stanbridge, E. J., Zavada, J., Kettmann, R., Pastorek, J. Human MN/CA9 gene, a novel member of the carbonic anhydrase family: structure and exon to protein domain relationships. Genomics 33: 480-487, 1996. [PubMed: 8661007] [Full Text: https://doi.org/10.1006/geno.1996.0223]
Pastorek, J., Pastorekova, S., Callebaut, I., Mornon, J. P., Zelnik, V., Opavsky, R., Zat'ovicova, M., Liao, S., Portetelle, D., Stanbridge, E. J., Zavada, J., Burny, A., Kettmann, R. Cloning and characterization of MN, a human tumor-associated protein with a domain homologous to carbonic anhydrase and a putative helix-loop-helix DNA binding segment. Oncogene 9: 2877-2888, 1994. [PubMed: 8084592]