Mutation analysis of the 8p22 candidate tumor suppressor gene ATIP/MTUS1 in hepatocellular carcinoma.
A high frequency of allelic loss affecting chromosome 8p and a minimal region of deletion at p21-22 have been previously reported in hepatocellular carcinoma (HCC), suggesting that at least one tumor suppressor gene is present in this region. In this study, we assessed whether the angiotensin II AT2 receptor interacting protein (ATIP)/mitochondrial tumor suppressor gene (MTUS1), a gene newly identified at position 8p22, may be a candidate tumor suppressor gene mutated in HCC. We searched for alterations in the 17 coding exons of ATIP/MTUS1 by means of denaturating high-performance liquid chromatography and sequencing, in 51 HCC tumors and 58 cell lines for which loss of heterozygosity status was known. Five major nucleotide substitutions were identified, all located in exons used by the ATIP3 transcript which is the only ATIP transcript variant expressed in liver. These nucleotide variations result in amino-acid substitution or deletion of conserved structural motifs (nuclear localisation signal, polyproline motif, leucine zipper) and also affect exonic splicing enhancer motifs and physiological splice sites, suggesting potential deleterious effects on ATIP3 function and/or expression.
Di Benedetto
M
M
Institut Cochin, Département de Biologie Cellulaire, Paris, F-75014 France.
Pineau
P
P
Nouet
S
S
Berhouet
S
S
Seitz
I
I
Louis
S
S
Dejean
A
A
Couraud
P O
PO
Strosberg
A D
AD
Stoppa-Lyonnet
D
D
Nahmias
C
C
D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D002898:Chromosomes, Human, Pair 8; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D016147:Genes, Tumor Suppressor; D014644:Genetic Variation; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012326:RNA Splicing; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D004273:DNA, Neoplasm; C474762:MTUS1 protein, human; D025521:Tumor Suppressor Proteins