The murine double minute 2 (mdm2) gene is essential for embryogenesis in mice that express the p53 tumor suppressor protein. Mdm2 levels must be regulated tightly because overexpression of mdm2 contributes to tumorigenesis. We investigated whether the 5′ and 3′ untranslated regions (UTRs) of murine mdm2 affect the expression of MDM2 proteins. Induction of mdm2 expression by p53 results in synthesis of an mdm2 mRNA with a short 5′ UTR. The long 5′ UTR increases internal initiation of translation of a minor MDM2 protein, p76MDM2, without affecting the efficiency of translation of the full-length p90MDM2. We discovered two alternative 3′ untranslated regions in murine mdm2 mRNA expressed in the testis. The longer 3′ UTR contains a consensus instability element, but mdm2 mRNAs containing the long and short 3′ UTRs have comparable half-lives. The 3′ UTRs do not affect either initiation codon use or translation efficiency. Thus, the murine 5′ UTR, but not the 3′UTR, influences the ratio of the two MDM2 proteins but neither UTR affects MDM2 abundance significantly.
Bibliographical noteFunding Information:
We thank Drs Donna George (University of Pennsylvania), Steve Jones (University of Massachusetts), and Moshe Oren (Weizmann Institute) for mdm2 plasmids. We are grateful to Andrew Kastenmeier and Dr Norman Drinkwater (McArdle Laboratory) for sequencing advice and for genomic DNA from multiple mouse strains. The helpful and critical comments of Dr Jeff Ross are very much appreciated. This work was supported by developmental funds from Cancer Center Support Grant CA-07175 to the McArdle Laboratory for Cancer Research and by NIH Grant CA-70718 to M.E.P. S.M.M. was supported by NCI Predoctoral Training Grant CA-09135 from the National Institutes of Health.
- RNA stability
- Translation efficiency
- Translational initiation
- Untranslated region