Regulation of ribonucleotide reductase M2 expression by the upstream AUGs

被引:21
作者
Dong, ZZ [1 ]
Liu, Y [1 ]
Zhang, JT [1 ]
机构
[1] Indiana Univ, Sch Med, Walther Canc Inst, Canc Ctr,Dept Pharmacol & Toxicol, Indianapolis, IN 46202 USA
关键词
D O I
10.1093/nar/gki569
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Ribonucleotide reductase catalyzes a rate-limiting reaction in DNA synthesis by converting ribonucleotides to deoxyribonucleotides. It consists of two subunits and the small one, M2 (or R2), plays an essential role in regulating the enzyme activity and its expression is finely controlled. Changes in the M2 level influence the dNTP pool and, thus, DNA synthesis and cell proliferation. M2 gene has two promoters which produce two major mRNAs with 5'-untranslated regions (5'-UTRs) of different lengths. In this study, we found that the M2 mRNAs with the short (63 nt) 5'-UTR can be translated with high efficiency whereas the mRNAs with the long (222 nt) one cannot. Examination of the long 5'-UTR revealed four upstream AUGs, which are in the same reading frame as the unique physiological translation initiation codon. Further analysis demonstrated that these upstream AUGs act as negative cis elements for initiation at the downstream translation initiation codon and their inhibitory effect on M2 translation is eIF4G dependent. Based on the findings of this study, we conclude that the expression of M2 is likely regulated by fine tuning the translation from the mRNA with a long 5'-UTR during viral infection and during the DNA replication phase of cell proliferation.
引用
收藏
页码:2715 / 2725
页数:11
相关论文
共 46 条
[1]   EFFECT OF CYCLIC-AMP ON THE CELL-CYCLE REGULATION OF RIBONUCLEOTIDE REDUCTASE M2 SUBUNIT MESSENGER-RNA CONCENTRATIONS IN WILD-TYPE AND MUTANT S49 T-LYMPHOMA CELLS [J].
ALBERT, DA ;
NODZENSKI, E ;
YIM, G ;
KOWALSKI, J .
JOURNAL OF CELLULAR PHYSIOLOGY, 1990, 143 (02) :251-256
[2]   Defining a novel cis-element in the 3'-untranslated region of mammalian ribonucleotide reductase component R2 mRNA - cis-trans-interactions and message stability [J].
Amara, FM ;
Sun, J ;
Wright, JA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (33) :20126-20131
[3]  
AMARA FM, 1994, J BIOL CHEM, V269, P6709
[4]   A stable HeLa cell line that inducibly expresses poliovirus 2Apro:: Effects on cellular and viral gene expression [J].
Barco, A ;
Feduchi, E ;
Carrasco, L .
JOURNAL OF VIROLOGY, 2000, 74 (05) :2383-2392
[5]  
BJORKLUND S, 1990, BIOCHEMISTRY-US, V29, P5452
[6]  
BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
[7]   Inhibition of human cancer cell growth by inducible expression of human ribonucleotide reductase antisense cDNA [J].
Chen, SY ;
Zhou, BS ;
He, FQ ;
Yen, Y .
ANTISENSE & NUCLEIC ACID DRUG DEVELOPMENT, 2000, 10 (02) :111-116
[8]   Role of eIF3 p170 in controlling synthesis of ribonucleotide reductase M2 and cell growth [J].
Dong, ZZ ;
Liu, LH ;
Han, BG ;
Pincheira, R ;
Zhang, JT .
ONCOGENE, 2004, 23 (21) :3790-3801
[9]   EIF3 p170, a mediator of mimosine effect on protein synthesis and cell cycle progression [J].
Dong, ZZ ;
Zhang, JT .
MOLECULAR BIOLOGY OF THE CELL, 2003, 14 (09) :3942-3951
[10]   ABROGATION OF TRANSLATION INITIATION-FACTOR EIF-2 PHOSPHORYLATION CAUSES MALIGNANT TRANSFORMATION OF NIH 3T3 CELLS [J].
DONZE, O ;
JAGUS, R ;
KOROMILAS, AE ;
HERSHEY, JWB ;
SONENBERG, N .
EMBO JOURNAL, 1995, 14 (15) :3828-3834