Inhibition of tumorigenicity by the 5'-untranslated RNA of the human c-myc P0 transcript.
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.
Blume
Scott W
SW
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
Miller
Donald M
DM
Guarcello
Vincenzo
V
Shrestha
Kedar
K
Meng
Zheng
Z
Snyder
Richard C
RC
Grizzle
William E
WE
Ruppert
J Michael
JM
Gartland
G Larry
GL
Stockard
Cecil R
CR
Jones
David E
DE
Emanuel
Peter D
PD
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
D020121:5' Untranslated Regions; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger