The Neurofibromatosis Type I Messenger RNA Undergoes Base-Modification RNA Editing

Abstract

A functional mooring sequence, known to be required for apolipoprotein B (apoB) mRNA editing, exists in the mRNA encoding the neurofibromatosis type I (NF1) tumor suppressor. Editing of NF1 mRNA modifies cytidine in an arginine codon (CGA) at nucleotide 2914 to a uridine (UGA), creating an in frame translation stop codon. NF1 editing occurs in normal tissue but was several-fold higher in tumors. In vitro editing and transfection assays demonstrated that apoB and NF1 RNA editing will take place in both neural tumor and hepatoma cells. Unlike apoB, NF1 editing did not demonstrate dependence on rate-limiting quantities of APOBEC-1 (the apoB editing catalytic subunit) suggesting that different trans-acting factors may be involved in the two editing processes.

Absence of APOBEC-1 mediated mRNA editing in human carcinomas

“…One ml of 1 : 100 diluted primary RT ± PCR was ampli®ed by nested PCR with oligonucleotides NF3 (GAC ATT CTG TTT CAA GGT ATA TGG TGC, sense, nt 2853 ± 2879) and NF4 (ATA AAC AGT GGC ACA CAC TTC GAA GTT G, antisense, nt 3103 ± 3076) for 25 cycles using the conditions as described above. The RT ± PCR products were analysed for editing by primer extension assay as described (Skuse et al, 1996). In addition, the RT ± PCR products for NF 1 mRNA were cloned and sequenced.…”

“…Further evidence that mRNA editing may be involved in tumorigenesis comes from studies in malignant neuro®bromas of patients with neuro®bromatosis type 1 (NF1) (Cappione et al, 1997). The mRNA of the NF1 gene has been demonstrated to be edited from C to U at nucleotide position 2914, creating a premature stop translation codon (Skuse et al, 1996). The editing of NF1 mRNA was much higher in neurofibromatous tumors as compared to normal tissues and it was concluded that mRNA editing may contribute to the genetic inactivation of the NF1 gene in NF1 malignancies (Cappione et al, 1997).…”

“…The editing of NF1 mRNA was much higher in neurofibromatous tumors as compared to normal tissues and it was concluded that mRNA editing may contribute to the genetic inactivation of the NF1 gene in NF1 malignancies (Cappione et al, 1997). Whether the editing of NF1 is mediated by APOBEC-1 together with novel trans-acting factors remains to be conclusively established (Skuse et al, 1996;Cappione et al, 1997). The third line of evidence that mRNA editing may be involved in oncogenesis is derived from an investigation of the Wilms tumor susceptibility gene WT1 (Sharma et al, 1994).…”

Pathophysiology of Neurofibromatosis Type 1

“…This includes finding loss of heterozygosity or homozygous mutation of the NF1 gene in benign neurofibromas [33], as well as many malignant tumors (summarized above). In addition, mice rendered heterozygous for an Nf1 mutation develop leukemias and sarcomas [71], and mice that are chimeric for cells with homozygous Nf1 mutation develop neurofibroma-like tumors [72]. Loss of neurofibromin function is probably a critical event in the formation of neurofibromas, but, at least in neural tissues, is not sufficient to result in malignancy.…”

Flow-cytometric visualization of C>U mRNA editing reveals the dynamics of the process in live cells

“…Subsequent studies have identified a number of other physiologically edited transcripts, mainly in the 3 0 untranslated regions. [8][9][10] While not directly affecting the coding sequence, these edited residues could affect the regulation of the transcript itself. 9,10 Other roles not linked to APOBEC1 ability to edit specific mRNAs have been suggested: regulation of mRNA stability, restriction of retroviruses and mobile elements, and active demethylation of DNA.…”