Novel MUC1 splice variants contribute to mucin overexpression in CFTR-deficient mice.
A cystic fibrosis (CF) mouse expressing the human mucin MUC1 transgene (CFM) reverted the CF/Muc1(-/-) phenotype (little mucus accumulated in the intestine) to that of CF mice expressing mouse Muc1, which exhibited increased mucus accumulation. Western blots and immunohistochemical analysis showed that the MUC1 protein was markedly increased in CFM mice in which it was both membrane bound and secreted into the intestinal lumen. Studies to determine the reason for increased levels of the extracellular domain of MUC1 mucin identified mRNA and protein of two novel splice variants and the previously described secreted MUC1 lacking the cytoplasmic tail (MUC1/SEC). Novel MUC1 splice variants, CT80 and CT58, were both transmembrane proteins with cytoplasmic tails different from the normal MUC1. The MUC1-CT80 and MUC1/SEC forms are found expressed mainly in the CFM mice intestines. Thus MUC1 expression is increased, and it appears that alternate cytoplasmic tails may change its role in signaling. MUC1 could be an important contributor to the CF intestinal phenotype.
Hinojosa-Kurtzberg
A Marina
AM
Mayo Clinic Scottsdale, Department of Biochemistry and Molecular Biology, Scottsdale, Arizona 85259, USA.
Johansson
Malin E V
ME
Madsen
Cathy S
CS
Hansson
Gunnar C
GC
Gendler
Sandra J
SJ
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000172:deficiency* / Q000235:genetics*; D007413:Intestinal Mucosa / Q000378:metabolism; D051379:Mice; D018181:Mice, Inbred CFTR; D009077:Mucins / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010641:Phenotype
D009077:Mucins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator