Genomic Instability and Evolution of Drug Resistance

基因组不稳定性和耐药性的演变

• 批准号: 7380083
• 负责人: MACUS T KUO
• 金额: $ 29.35万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7380083
• 关键词: 1q31; Affect; Amino Acids; Animals; Bladder; Cell Aging; Cell Death; Cell Nucleus; Cells; Chromosome Breakage; Chromosome Fragile Sites; Chromosome abnormality; Colon; Complementary DNA; Cultured Cells; Cytoplasm; DNA; DNA amplification; Development; Differentiation and Growth; Drug resistance; Epithelial; Epithelial Cells; Epithelium; Event; Evolution; Gene Amplification; Genes; Genomic Instability; Genus Cola; Human; Knock-out; Learning; Length; Localized; Malignant - descriptor; Malignant Epithelial Cell; Mammalian Cell; Mammary gland; Messenger RNA; Mitotic; Molecular; Mouse Strains; Multi-Drug Resistance; Neoplastic Cell Transformation; Open Reading Frames; Organ; Ovary; Pattern; Physiology; Play; Process; Prostate; Proteins; Recombinants; Role; Sequence Analysis; Source; Staging; Structure; System; Testing; Tissues; Transfection; Variant; cancer cell; cell growth; cell growth regulation; cell type; chemotherapy; drug sensitivity; embryonic stem cell; expression vector; gene function; insight; novel; programs; senescence

DESCRIPTION (provided by applicant): DNA amplification is frequently observed in cancer cells and in drug-resistant cells. One important mechanism involved in DNA amplification is the breakage-fusion-bridge (BFB) process. We previously demonstrated that chromosomal fragile site breakage triggers the BFB cycle. In many CHO multidrug-resistant cells, amplification of mdr1 is associated with the breakage of chromosomal fragile site 1q31. To learn the molecular mechanism underlying the initial events of mdrl amplification, we have cloned 1q31 fragile site DNA. Strikingly, we found that this fragile site contains a novel gene, designated as fragile site associated (fsa) gene, Fas encodes a mRNA of greater than14 kb. Full-length human FSA cDNA has been cloned. Sequence analyses revealed that its mRNA is bicistronic and contains two evolutionarily conserved nonoverlapping open reading frames (orf1 and orf2). While basal levels of FSA mRNA seem to express in many cell types, immunohistochemical analyses revealed a co-expression pattern of the two off-encoded proteins in the post-mitotic, well-differentiated epithelial compartments of many organs; including colon, mammary glands, ovary, prostate and bladder. These findings suggest that FSA plays important roles in, regulating mammalian epithelial growth and differentiation. Moreover, in normal mature epithelia, the FSA protein seems to be localized in nuclei, whereas in the malignant cells of epithelial origins, FSA seems to be mainly cytoplasmic. These results suggest a nucleus-cytoplasm shuffling during epithelial transformation. We hypothesize that elevated FSA expression may induce premature senescence and affect drug sensitivities to chemotherapy of epithelial cells. We propose three specific aims to further elucidate the structure/function of this gene. In Aim I, we propose to critically re-investigate the intracellular localizations of FSA-orf1 and FSA-orf2, and their expression in normal and malignant epithelial cells from many tissue sources. In Aim II, we propose to investigate the function of FSA-orf1 and FSA-ort2 in cultured cells by transfection and to test the above-mentioned hypothesis. And in Aim III, we propose to investigate the function of FSA-orf1 and FSA-orf2 using the knock out strategies. We anticipate from these studies to gain important insights into the function of FSA in the regulation of cell growth and differentiation in normal and malignant epithelial cells.

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