Characterization of a reciprocal-like translocation involving 6q in a melanoma cell line

Ms Jackie Fung (2008). Characterization of a reciprocal-like translocation involving 6q in a melanoma cell line PhD Thesis, School of Molecular and Microbial Sciences, The University of Queensland.

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Author Ms Jackie Fung
Thesis Title Characterization of a reciprocal-like translocation involving 6q in a melanoma cell line
School, Centre or Institute School of Molecular and Microbial Sciences
Institution The University of Queensland
Publication date 2008-10
Thesis type PhD Thesis
Supervisor Prof. Ross Smith
Prof. Xin Yuan Guan
Dr. Melissa Brown
Total pages 161
Total colour pages 19
Total black and white pages 142
Subjects 270000 Biological Sciences
Abstract/Summary Deletion of the long arm of chromosome 6 is one of the most common genetic alterations in human malignant melanoma. Recently, a reciprocal translocation between chromosomes 6q and 17p was detected in a melanoma cell line, UACC-930, using arm painting probes of 6p and 6q. Reciprocal translocation is seldom observed in solid tumors. Upon further characterization of the translocation marker using techniques such as Southern blotting, genomic library screening and DNA sequencing, a complex rearrangement including two inversions of 6q and a translocation between the inverted 6q and 17p, [der(6)inv(6)(q21q22)(q22q27)t(6;17)(q27;p13)], was detected. An NCBI blast search revealed 3 genes being interrupted by the breakpoints: prenyl diphosphate synthase subunit 2 (PDSS2) at 6q21, Parkin at 6q27 and p53 at 17p13. Down-regulation of PDSS2 was commonly observed in 59/87 (67.8%) primary melanomas, which was significantly higher than that in benign nevi (7/66, 10.6%, p<0.001), indicating the tumor-suppressive potential of PDSS2 in melanoma development. To characterize the function of PDSS2 in tumorigenesis, PDSS2 was stably transfected into a highly tumorigenic melanoma cell line, UACC-903. The tumor-suppressive function of PDSS2 was demonstrated by both in vitro and in vivo assays. The results showed that PDSS2 could inhibit tumor cell growth, decrease the colony-forming ability in soft agar, and totally abrogate the tumorigenicity of UACC-903 in nude mice. PDSS2 is the first enzyme involved in the CoQ10 biosynthesis pathway. Other studies have demonstrated PDSS2 mutations can cause severe CoQ10 deficiency and markedly reduced ATP production because of respiratory chain dysfunction. Interestingly, proteomics analysis revealed 7 out of 11 identified proteins (HSPA8, GAPDHS, TPI1, HSPA5, PGK1, ENO1, and ATP5B) differentially expressed in PDSS2-overexpressing cells were related to energy metabolism. Further studies are required to determine how PDSS2 could alter the energy supply in tumor cells. Taken together, these results support the proposal that PDSS2 is a novel tumor suppressor gene which may play an important role in the development of malignant melanoma via altering tumor metabolism.
Keyword PDSS2
melanoma, tumor suppressor gene
translocation breakpoint
Additional Notes Colour pages: 38, 45, 75-77, 79, 93, 95-96, 99-101, 107, 109-110, 118, 125-126, 135 Landscape pages: 32, 35, 76-77, 119, 125-126

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Created: Wed, 29 Apr 2009, 17:09:55 EST by Ms Jackie Fung on behalf of Library - Information Access Service