Microsatellite deletions in the c-myb transcriptional attenuator region associated with over-expression in colon tumour cell lines.
In the hemopoietic system c-myb expression is required for proliferation of immature cells and its down-regulation is required for differentiation. In colonic mucosa c-myb expression occurs at levels comparable to immature hemopoietic cells. Inhibition of c-myb expression in colon cell lines, using anti-sense oligonucleotides, indicates that c-myb expression is required for proliferation. However, the mechanism of c-myb regulation during colon cell differentiation has not been explored. Using the LIM1215 and CaCo-2 colon carcinoma cell lines induced to differentiate with sodium butyrate, we demonstrate that c-myb mRNA is down-regulated as an early event in differentiation by a mechanism involving transcriptional attenuation in intron 1. By analogy with procaryotic and eucaryotic genes, transcriptional attenuation probably occurs in a region containing nineteen consecutive thymidine residues. Computer prediction of the secondary structure of the nascent mRNA chain encoded by this region suggests a strong potential for stem-loop formation. Sequence analysis of several colon tumour cell lines reveals mutations in this region that may disrupt transcriptional attenuation and result in the increased c-myb expression observed in colon tumours and tumour cell lines.
Thompson
M A
MA
Ludwig Institute for Cancer Research, PO Royal Melbourne Hospital, Australia.
Flegg
R
R
Westin
E H
EH
Ramsay
R G
RG
D001483:Base Sequence; D002454:Cell Differentiation; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006860:Hydrogen Bonding; D007438:Introns; D018895:Microsatellite Repeats; D009690:Nucleic Acid Conformation; D009876:Operon; D018807:Polymorphism, Single-Stranded Conformational; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D020598:Proto-Oncogene Proteins c-myb; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D017384:Sequence Deletion; D015534:Trans-Activators / Q000235:genetics*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D011518:Proto-Oncogene Proteins; D020598:Proto-Oncogene Proteins c-myb; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D015534:Trans-Activators