title: Inhibition of tumorigenicity by the 5'-untranslated RNA of the human c-myc P0 transcript.
abstract: Activity of the independently regulated human c-myc P0 promoter has been associated with the undifferentiated status of leukemia cells as well as the hormone-independent proliferation of breast cancer cells. The P0 transcript is distinguished from the predominant P1 and P2 c-myc mRNAs by an approximately 639-nucleotide extension of the 5'-untranslated region. We hypothesized that this complex 5'-untranslated RNA sequence unique to the P0 transcript may contribute significantly to the composite regulation of the c-myc locus and that enforced intracellular synthesis of the isolated P0 5'-UTR, out of its native sequence context, might amplify or dominantly interfere with its normal regulatory function. Human tumor (HeLa) cells in which the isolated P0 5'-UTR was ectopically expressed displayed a dramatic decrease in anchorage-independent proliferation. Furthermore, P0 5'-UTR-expressing HeLa cells failed to form tumors when inoculated into SCID mice. This loss of tumorigenicity was associated with increases in levels of the c-Myc1 (p67) and c-Myc2 (p64) proteins and a 3- to 5-fold elevation of spontaneous apoptotic index. These results demonstrate that an isolated 5'-untranslated RNA sequence can be attributed potent in trans gene-regulatory and phenotype-altering capabilities and that extrinsic alterations in c-myc regulation can be utilized to reestablish the natural proapoptotic (tumor suppressor) activities associated with this protooncogene.
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Tumor Institute, Room 508, 1824 6th Avenue South, Birmingham, AL 35294-3300, USA. scott.blume@ccc.uab.edu
authors.forename: Scott W
authors.initials: SW
authors.lastname: Blume
authors.forename: Donald M
authors.initials: DM
authors.lastname: Miller
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Guarcello
authors.forename: Kedar
authors.initials: K
authors.lastname: Shrestha
authors.forename: Zheng
authors.initials: Z
authors.lastname: Meng
authors.forename: Richard C
authors.initials: RC
authors.lastname: Snyder
authors.forename: William E
authors.initials: WE
authors.lastname: Grizzle
authors.forename: J Michael
authors.initials: JM
authors.lastname: Ruppert
authors.forename: G Larry
authors.initials: GL
authors.lastname: Gartland
authors.forename: Cecil R
authors.initials: CR
authors.lastname: Stockard
authors.forename: David E
authors.initials: DE
authors.lastname: Jones
authors.forename: Peter D
authors.initials: PD
authors.lastname: Emanuel
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D012333:RNA, Messenger / Q000494:pharmacology*; D014162:Transfection
chemical_list: D020121:5' Untranslated Regions; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger