Allele-specific loss of heterozygosity at the DAL-1/4.1B (EPB41L3) tumor-suppressor gene locus in the absence of mutation.
DAL-1/4.1B (EPB41L3)is a member of the protein 4.1 superfamily, which encompasses structural proteins that play important roles in membrane processes via interactions with actin, spectrin, and the cytoplasmic domains of integral membrane proteins. DAL-1/4.1B localizes within chromosomal region 18p11.3, which is affected by loss of heterozygosity (LOH) in various adult tumors. Reintroduction of this protein into DAL-1/4.1B-null lung and breast tumor cell lines significantly reduced the number of cells, providing functional evidence that this protein possesses a growth suppressor function not confined to a single cell type. For characterization of the mutational mechanisms responsible for loss of DAL-1/4.1B function in tumors, the exon-intron structure of DAL-1/4.1B was examined for mutations in 15 normal/tumor pairs of non-small cell lung carcinoma by single-strand conformation polymorphism analysis. These studies revealed that small intragenic mutations are uncommon in DAL-1/4.1B. Furthermore, LOH analysis on 129 informative early-stage breast tumors utilizing a new intragenic C/T single-nucleotide polymorphism in exon 14 revealed that LOH resulted in preferential retention of the C-containing allele, suggesting that allele-specific loss is occurring. These studies indicate that mechanisms such as imprinting or monoallelic expression in combination with loss of heterozygosity may be responsible for loss of the DAL-1/4.1B protein in early breast disease.
Kittiniyom
Kanokwan
K
David and Doreen Hermelin Laboratory of Molecular Oncogenetics, Hermelin Brain Tumor Center and Department of Neurosurgery, Henry Ford Hospital, Detroit, Michigan 48202, USA.
Mastronardi
Michelle
M
Roemer
Martha
M
Wells
Wendy A
WA
Greenberg
E Robert
ER
Titus-Ernstoff
Linda
L
Newsham
Irene F
IF
D000328:Adult; D000409:Alanine / Q000235:genetics / Q000502:physiology; D000483:Alleles; D000595:Amino Acid Sequence / Q000235:genetics; D019943:Amino Acid Substitution / Q000235:genetics / Q000502:physiology; D000818:Animals; D001483:Base Sequence / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis / Q000379:methods; D004273:DNA, Neoplasm / Q000235:genetics; D005091:Exons / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D016147:Genes, Tumor Suppressor; D005819:Genetic Markers / Q000235:genetics*; D018392:Genomic Imprinting / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics; D019656:Loss of Heterozygosity / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D008565:Membrane Proteins; D051379:Mice; D008840:Microfilament Proteins; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018807:Polymorphism, Single-Stranded Conformational; D011506:Proteins / Q000235:genetics*; D012694:Serine / Q000235:genetics / Q000502:physiology; D025521:Tumor Suppressor Proteins
D004273:DNA, Neoplasm; C116887:EPB41L3 protein, human; D005819:Genetic Markers; D008565:Membrane Proteins; D008840:Microfilament Proteins; D011506:Proteins; D025521:Tumor Suppressor Proteins; D012694:Serine; D000409:Alanine