Inhibition of tumorigenicity by the 5'-untranslated RNA of the human c-myc P0 transcript.

Academic Article

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.
  • Published In

    Keywords

  • 5' Untranslated Regions, Animals, Apoptosis, Base Sequence, Cell Division, Gene Expression Regulation, Neoplastic, HeLa Cells, Humans, Mice, Mice, SCID, Neoplasm Transplantation, Proto-Oncogene Proteins c-myc, RNA, Messenger, Transfection
  • Author List

  • Blume SW; Miller DM; Guarcello V; Shrestha K; Meng Z; Snyder RC; Grizzle WE; Ruppert JM; Gartland GL; Stockard CR
  • Start Page

  • 131
  • End Page

  • 142
  • Volume

  • 288
  • Issue

  • 1