Dihydrofolate reductase protein inhibits its own translation by binding to dihydrofolate reductase mRNA sequences within the coding region.
Previous studies suggest that dihydrofolate reductase (DHFR) regulates its own translation. Moreover, intracellular levels of DHFR protein increase following exposure to the antifolate methotrexate (MTX), suggesting that MTX may release the translational inhibition mediated by DHFR [Chu et al. (1993) Biochemistry 32,4756-4760; Ercikan et al. (1993) Adv. Exp. Med. Biol. 338, 537-540]. To further investigate the role of DHFR in translational autoregulation, we have considered the possibility that DHFR directly contacts its cognate mRNA. Binding studies using a series of truncated DHFR mRNAs as probes localized the DHFR/RNA interaction to a 100-base-pair region containing two putative stem-loop structures; initial studies indicated that both of these loop structures are involved in protein binding. Moreover, the binding of MTX to DHFR prevents interaction of the protein with its cognate mRNA, thereby relieving translational autoregulation.
Ercikan-Abali
E A
EA
Program of Molecular Pharmacology and Therapeutics, Cornell University Medical College, Memorial Sloan-Kettering Cancer Center, New York 10021, USA.
Banerjee
D
D
Waltham
M C
MC
Skacel
N
N
Scotto
K W
KW
Bertino
J R
JR
D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D003062:Codon / Q000187:drug effects / Q000378:metabolism*; D005493:Folic Acid Antagonists / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000235:genetics; D014176:Protein Biosynthesis / Q000187:drug effects*; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000494:pharmacology; D013762:Tetrahydrofolate Dehydrogenase / Q000187:drug effects / Q000235:genetics* / Q000494:pharmacology*
D003062:Codon; D005493:Folic Acid Antagonists; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D012313:RNA; D013762:Tetrahydrofolate Dehydrogenase