Abstract

The rates of synthesis of the polyamines (spermidine and spermine) and their metabolic precursor putrescine are increased during the proliferative response of mammalian cells and elevated levels of these compounds are necessary for optimal cell growth. Two key enzymes of polyamine biosynthesis, ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (SDC), are regulated during this process. We have shown that the synthesis of these two proteins is regulated by both the levels and efficiency of translation of their respective mRNAs. In this application we propose to define the structure of the SDC gene and the mRNAs that are synthesized from it. The level of SDC mRNA is regulated post-transcriptionally and the mechanism of this will be studied. In addition, we will further characterize the mechanism of the control of translation of both ODC and SDC mRNAs through the use of in vitro mutagenesis and gene transfer techniques.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA039053-07
Application #
3177752
Study Section
Biochemistry Study Section (BIO)
Project Start
1984-07-01
Project End
1992-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
7
Fiscal Year
1990
Total Cost
Indirect Cost

  Institution

Name
University of Washington
Department
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195

  Publications

Raney, Alexa; Law, G Lynn; Mize, Gregory J et al. (2002) Regulated translation termination at the upstream open reading frame in s-adenosylmethionine decarboxylase mRNA. J Biol Chem 277:5988-94
Law, G L; Raney, A; Heusner, C et al. (2001) Polyamine regulation of ribosome pausing at the upstream open reading frame of S-adenosylmethionine decarboxylase. J Biol Chem 276:38036-43
Mize, G J; Morris, D R (2001) A mammalian sequence-dependent upstream open reading frame mediates polyamine-regulated translation in yeast. RNA 7:374-81
Morris, D R; Geballe, A P (2000) Upstream open reading frames as regulators of mRNA translation. Mol Cell Biol 20:8635-42
Raney, A; Baron, A C; Mize, G J et al. (2000) In vitro translation of the upstream open reading frame in the mammalian mRNA encoding S-adenosylmethionine decarboxylase. J Biol Chem 275:24444-50
Brown, C Y; Mize, G J; Pineda, M et al. (1999) Role of two upstream open reading frames in the translational control of oncogene mdm2. Oncogene 18:5631-7
Link, A J; Eng, J; Schieltz, D M et al. (1999) Direct analysis of protein complexes using mass spectrometry. Nat Biotechnol 17:676-82
Mize, G J; Ruan, H; Low, J J et al. (1998) The inhibitory upstream open reading frame from mammalian S-adenosylmethionine decarboxylase mRNA has a strict sequence specificity in critical positions. J Biol Chem 273:32500-5
Ruan, H; Shantz, L M; Pegg, A E et al. (1996) The upstream open reading frame of the mRNA encoding S-adenosylmethionine decarboxylase is a polyamine-responsive translational control element. J Biol Chem 271:29576-82
Morris, D R (1995) Growth control of translation in mammalian cells. Prog Nucleic Acid Res Mol Biol 51:339-63

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