Disabled-1 is a large common fragile site gene, inactivated in multiple cancers.
Common fragile sites (CFS) are large, genomically unstable regions, which are hot-spots for deletions and other alterations, especially in cancer cells. Several have been shown to contain genes that span large genomic regions, such as FHIT (1.5 Mb), WWOX (1.0 Mb), GRID2 (1.36 Mb), PARK2 (1.3 Mb), and RORA (730 kb). These genes are frequently inactivated in multiple different cancers, and FHIT and WWOX are shown to function as tumor suppressors. The disabled-1 gene (DAB1) is one of the human homologs of the Drosophila disabled locus, which in mammals is involved in neuronal migration and lamination in the developing cerebral cortex. Mice DAB1 inactivation results in the neurological mutant Scrambler, having similarities to mice with the inactivation of PARK2 (Quaker), GRID2 (Lurcher), and RORA (Staggerer). We were interested in whether DAB1 was another large CFS gene that could have cancer development importance. We demonstrated here that the human DAB1 gene (spanning 1.25 Mb) mapped within FRA1B CFS region on chromosomal band 1p32.2. Real-time RT-PCR analysis revealed that the expression level of DAB1 was decreased in many human cancer samples, including primary tumor tissues and cancer-derived cell lines, from several different cancers, especially in brain and endometrial cancer. Additionally, the introduction of an over-expression DAB1 plasmid into two different cell lines, having insignificant endogenous DAB1 expression, resulted in decreased cell growth. In summary, DAB1 is another gene that resides within an unstable CFS region and might play a role in human tumorigenesis. These data may provide further linkage between neurological development and cancer.
McAvoy
Sarah
S
Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55902, USA.
Zhu
Yu
Y
Perez
Damon S
DS
James
C David
CD
Smith
David I
DI
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D043283:Chromosome Fragile Sites / Q000235:genetics*; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; C115785:DAB1 protein, human; C103773:Dab1 protein, mouse; D009419:Nerve Tissue Proteins