Role of Two Upstream Open Reading Frames in the Translational Control of
Oncogene mdm2
Cheryl Y. Brown, Gregory J. Mize, Mario Pineda, Donna L. George and David
R. Morris
Overexpression of oncoprotein MDM2 has been found in a significant number
of human soft tissue tumors. In a subset of these tumors, overexpression
is a result of enhanced translation of mdm2 mRNA. There are two transcripts
from the mdm2 gene that differ only in their 5' leaders: a long form (L-mdm2)
and a short form (S-mdm2) that arise from the use of different promoters.
L-mdm2 mRNA contains two upstream open reading frames form (L-mdm2) and
a short form (S-mdm2) that arise from the use of different promoters. L-mdm2
mRNA contains two upstream open reading frames (uORFs) and this mRNA was
loaded with ribosomes inefficiently in comparison with S-mdm2. The 5' leader
of L-mdm2 was sufficient to transfer translational repression to a reporter
gene and the two uORFs acted synergistically to achieve full suppression.
In contrast, the 5' leader of S-mdm2 allowed efficient translation of an
attached reporter gene in the tumor cells. These results are consistent
with a model in which overexpression of MDM2 in certain tumors results
from a change in mRNA structure due to a switch in promoter usage.