Loss of heterozygosity on 8p in prostate cancer implicates a role for dematin in tumor progression.
Dematin is a cytoskeletal protein that bundles actin filaments in a phosphorylation-dependent manner. The primary structure of dematin is organized into an N-terminal core domain of unknown function and a C-terminal domain that is homologous to the "headpiece" domain of villin. We have previously localized the dematin gene on human chromosome 8p21.1, a region distal to the ankyrin locus for hereditary spherocytosis. Radiation hybrid mapping now places dematin between D8S258 and D8S137, two microsatellite markers frequently deleted in prostate cancer. The 8p21.1 region is also deleted in prostate, breast, colon, and bladder cancers, suggesting the presence of a tumor suppressor gene(s). Using laser-capture microdissection technique and fluorescence in situ hybridization (FISH), we demonstrate loss of heterozygosity (LOH) of the dematin gene in a majority of chromosomal region 8p21-linked prostate tumors. One allele of dematin was also deleted in the established prostate adenocarcinoma cell line PC-3, which displays a classic oncogenic phenotype. Overexpression of wild-type dematin in PC-3 cells resulted in the restoration of a more polarized, epithelial-like phenotype. Conversely, the heterologous expression of dominant negative mutants of dematin perturbed normal cell morphology of NIH 3T3 fibroblasts. These results suggest a biological function of dematin in the regulation of cell shape, with implications in the pathobiology of prostate tumorigenesis.
Lutchman
M
M
Section of Hematology/Oncology Research, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA.
Pack
S
S
Kim
A C
AC
Azim
A
A
Emmert-Buck
M
M
van Huffel
C
C
Zhuang
Z
Z
Chishti
A H
AH
D016475:3T3 Cells; D000818:Animals; D001798:Blood Proteins / Q000235:genetics / Q000502:physiology*; D002898:Chromosomes, Human, Pair 8; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins; D016373:DNA, Antisense / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D008840:Microfilament Proteins; D008957:Models, Genetic; D010641:Phenotype; D010750:Phosphoproteins; D020161:Physical Chromosome Mapping; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics*; D014407:Tumor Cells, Cultured
D001798:Blood Proteins; D003598:Cytoskeletal Proteins; C044805:DMTN protein, human; D016373:DNA, Antisense; C489041:Dmtn protein, mouse; D008840:Microfilament Proteins; D010750:Phosphoproteins