title: SIGLEC12, a human-specific segregating (pseudo)gene, encodes a signaling molecule expressed in prostate carcinomas.
abstract: The primate SIGLEC12 gene encodes one of the CD33-related Siglec family of signaling molecules in immune cells. We had previously reported that this gene harbors a human-specific missense mutation of the codon for an Arg residue required for sialic acid recognition. Here we show that this R122C mutation of the Siglec-XII protein is fixed in the human population, i.e. it occurred prior to the origin of modern humans. Additional mutations have since completely inactivated the SIGLEC12 gene in some but not all humans. The most common inactivating mutation with a global allele frequency of 58% is a single nucleotide frameshift that markedly shortens the open reading frame. Unlike other CD33-related Siglecs that are primarily found on immune cells, we found that Siglec-XII protein is expressed not only on some macrophages but also on various epithelial cell surfaces in humans and chimpanzees. We also found expression on certain human prostate epithelial carcinomas and carcinoma cell lines. This expression correlates with the presence of the nonframeshifted, intact SIGLEC12 allele. Although SIGLEC12 allele status did not predict prostate carcinoma incidence, restoration of expression in a prostate carcinoma cell line homozygous for the frameshift mutation induced altered regulation of several genes associated with carcinoma progression. These stably transfected Siglec-XII-expressing prostate cancer cells also showed enhanced growth in nude mice. Finally, monoclonal antibodies against the protein were internalized by Siglec-XII-expressing prostate carcinoma cells, allowing targeting of a toxin to such cells. Polymorphic expression of Siglec-XII in humans thus has implications for prostate cancer biology and therapeutics.
authors.affiliation: Glycobiology Research and Training Center, Department of Medicine, University of California at San Diego, La Jolla, California 92093, USA.
authors.forename: Nivedita
authors.initials: N
authors.lastname: Mitra
authors.forename: Kalyan
authors.initials: K
authors.lastname: Banda
authors.forename: Tasha K
authors.initials: TK
authors.lastname: Altheide
authors.forename: Lana
authors.initials: L
authors.lastname: Schaffer
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Johnson-Pais
authors.forename: Joke
authors.initials: J
authors.lastname: Beuten
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Leach
authors.forename: Takashi
authors.initials: T
authors.lastname: Angata
authors.forename: Nissi
authors.initials: N
authors.lastname: Varki
authors.forename: Ajit
authors.initials: A
authors.lastname: Varki
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D006801:Humans; D037102:Lectins / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011544:Pseudogenes; D014183:Transplantation, Heterologous
chemical_list: D037102:Lectins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C432400:SIGLEC12 protein, human