p190-A, a human tumor suppressor gene, maps to the chromosomal region 19q13.3 that is reportedly deleted in some gliomas.
To date, two distinct genes coding for Ras GAP-binding phosphoproteins of 190kDa, p190-A and p190-B, have been cloned from mammalian cells. Rat p190-A of 1513 amino acids shares 50% sequence identity with human p190-B of 1499 amino acids. We have previously demonstrated, using rat p190-A cDNA, that full-length p190-A is a tumor suppressor, reversing v-Ha-Ras-induced malignancy of NIH 3T3 cells through both the N-terminal GTPase (residues 1-251) and the C-terminal Rho GAP (residues 1168-1441) domains. Here we report the cloning of the full-length human p190-A cDNA and its first exon covering more than 80% of this protein, as well as its chromosomal mapping. Human p190-A encodes a protein of 1514 amino acids, and shares overall 97% sequence identity with rat p190-A. Like the p190-B exon, the first exon of p190-A is extremely large (3.7 kb in length), encoding both the GTPase and middle domains (residues 1-1228), but not the remaining GAP domain, suggesting a high conservation of genomic structure between two p190 genes. Using a well characterized monochromosome somatic cell hybrid panel, fluorescent in situ hybridization (FISH) and other complementary approaches, we have mapped the p190-A gene between the markers D19S241E and STD (500 kb region) of human chromosome 19q13.3. Interestingly, this chromosomal region is known to be rearranged in a variety of human solid tumors including pancreatic carcinomas and gliomas. Moreover, at least 40% glioblastoma/astrocytoma cases with breakpoints in this region were previously reported to show loss of the chromosomal region encompassing p190-A, suggesting the possibility that loss or mutations of this gene might be in part responsible for the development of these tumors.
Tikoo
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Ludwig Institute for Cancer Research, P.O. Box 2008, Royal Melbourne Hospital, Parkville, 3050, Melbourne, Australia.
Czekay
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Viars
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White
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Heath
J K
JK
Arden
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Maruta
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H
D000595:Amino Acid Sequence; D001483:Base Sequence; D002871:Chromosome Banding; D002874:Chromosome Mapping; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics*; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000737:chemistry / Q000235:genetics; D004268:DNA-Binding Proteins; D005091:Exons; D019204:GTP-Binding Proteins; D020690:GTPase-Activating Proteins; D017353:Gene Deletion; D005796:Genes / Q000235:genetics; D016147:Genes, Tumor Suppressor / Q000235:genetics*; D005910:Glioma / Q000235:genetics*; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007438:Introns; D008969:Molecular Sequence Data; D021101:Radiation Hybrid Mapping; D012097:Repressor Proteins; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D025521:Tumor Suppressor Proteins; D020703:ras GTPase-Activating Proteins / Q000235:genetics*; D020666:ras-GRF1
C074560:ARHGAP35 protein, human; C513043:ARHGAP5 protein, human; C513040:Arhgap35 protein, rat; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; C513039:RASGRF1 protein, human; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D020703:ras GTPase-Activating Proteins; D020666:ras-GRF1; D019204:GTP-Binding Proteins