Carbonic Anhydrase Related Protein VIII and its Role in Neurodegeneration and Cancer

Ashok      Aspatwar; Martti      E.E. Tolvanen; Csaba      Ortutay; Seppo      Parkkila

Abstract

Mammalian carbonic anhydrase (α-CA) gene family comprises sixteen isoforms, thirteen of which are active isozymes and three isoforms lack classical CA activity of reversible hydration of CO2 due to absence of one or more histidine residues required for CA catalytic activity. The inactive isoforms are known as carbonic anhydrase related proteins (CARPs) VIII, X and XI. Among these three, CARP VIII was reported first in 1990 from a mouse brain cDNA library and is well studied structurally as well as functionally compared to CARP X and XI. CARP VIII is an intriguing protein and is widely distributed and evolutionarily well-conserved across the species. It is mainly expressed in the Purkinje cells of cerebellum and in wide variety of other tissues both in mouse and human. CARP VIII has been linked to development of colorectal and lung cancers in humans, and overexpression of CARP VIII has been observed in several other cancers. A mutation in the CA8 gene has been associated with ataxia, mild mental retardation and quadrupedal gait in humans and with lifelong gait disorder in mice, suggesting an important role for CARP VIII in the brain. However, the precise function of CARP VIII is still an enigma. The present review article describes the previous data on CARP VIII, including its structure, role in neurodegeneration and cancer; and bioinformatic and expression analyses recently performed in our laboratory.

Keywords: Carbonic anhydrase related proteins, carbonic anhydrases, phylogenetics, structure, expression, neurodegeneration, cancer, Mammalian carbonic anhydrase (1-CA), isozymes, Purkinje cells, cerebellum, ataxia, quadrupedal gait, bioinformatic, fluorescence, chromosome, glutathione-S-transferase fusion protein (GST-HCARP VIII), higher molecular weight, SDS-PAGE, guanidine hydrochloride (GuHCl), Strongylocentrotus, Paracentrotus lividus, phylogenetic tree, animal taxonomy, orthologs, protostomes, isoleucines, inositol 1,4,5-trisphosphate (IP3), receptor type 1 (IP3R1), Ca2+ signaling, synapse recycling, proliferation, fertilization, synaptogenesis, colon cancers, neoplastic cells, malignant neoplasms, proapoptotic signals, adenoma specimens, adenocarcinomas, Paraneoplastic syndrome, breast carcinomas, paraneoplastic cerebellar degeneration (PCD), single nucleotide polymorphisms (SNPs), bone mineral density (BMD)