Transitional Regulation of HER2 Gene Expression.
Final rept. 1 Dec 96-30 Nov 98,
FRED HUTCHINSON CANCER RESEARCH CENTERSEATTLE WA
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Amplification of the HER2 gene occurs in more than 20 of breast cancers and is associated with aggressive tumor growth. Additional genetic mechanisms including translational deregulation may contribute to overexpression of the HER2 oncoprotein. The HER2 mRNA contains a conserved short upstream open reading frame that represses downstream translation in mammalian cells, in cell free extracts and in S. cerevisiae. The inhibitory effect of the upstream open reading frame does not depend on the precise 5 end of the mRNA, the uORF coding sequences or the nature of the downstream cistron. Rather, the naturally short intercistronic spacing between the upstream open reading frame and the HER2 coding region is critical for its inhibitory effect. Ribosomes that have translated the upstream open reading frame are able to reinitiate only inefficiently at the HER2 initiation codon but may reinitiate further downstream. These studies demonstrate that the uORF has a major repressive impact on HER2 protein expression.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research