A fission yeast homolog of Int-6, the mammalian oncoprotein and eIF3 subunit, induces drug resistance when overexpressed.
Through a screen to identify genes that induce multi-drug resistance when overexpressed, we have identified a fission yeast homolog of Int-6, a component of the human translation initiation factor eIF3. Disruption of the murine Int-6 gene by mouse mammary tumor virus (MMTV) has been implicated previously in tumorigenesis, although the underlying mechanism is not yet understood. Fission yeast Int6 was shown to interact with other presumptive components of eIF3 in vivo, and was present in size fractions consistent with its incorporation into a 43S translation preinitiation complex. Drug resistance induced by Int6 overexpression was dependent on the AP-1 transcription factor Pap1, and was associated with increased abundance of Pap1-responsive mRNAs, but not with Pap1 relocalization. Fission yeast cells lacking the int6 gene grew slowly. This growth retardation could be corrected by the expression of full length Int6 of fission yeast or human origin, or by a C-terminal fragment of the fission yeast protein that also conferred drug resistance, but not by truncated human Int-6 proteins corresponding to the predicted products of MMTV-disrupted murine alleles. Studies in fission yeast may therefore help to explain the ways in which Int-6 function can be perturbed during MMTV-induced mammary tumorigenesis.
Crane
R
R
Imperial Cancer Research Fund, Molecular Oncology Laboratory, University of Oxford, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom.
Craig
R
R
Murray
R
R
Dunand-Sauthier
I
I
Humphrey
T
T
Norbury
C
C
D000595:Amino Acid Sequence; D001483:Base Sequence; D050976:Basic-Leucine Zipper Transcription Factors; D001562:Benzimidazoles / Q000494:pharmacology; D002219:Carbamates; D002455:Cell Division / Q000235:genetics; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004352:Drug Resistance, Microbial / Q000235:genetics*; D039621:Eukaryotic Initiation Factor-3; D005656:Fungal Proteins / Q000235:genetics* / Q000378:metabolism; D005659:Fungicides, Industrial / Q000494:pharmacology; D015966:Gene Expression Regulation, Fungal; D006801:Humans; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D008969:Molecular Sequence Data; D000073718:Pancreatitis-Associated Proteins; D010448:Peptide Initiation Factors / Q000235:genetics* / Q000378:metabolism; D039665:Prokaryotic Initiation Factor-3; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012568:Schizosaccharomyces / Q000187:drug effects / Q000235:genetics*; D029702:Schizosaccharomyces pombe Proteins; D017386:Sequence Homology, Amino Acid; D015854:Up-Regulation
D050976:Basic-Leucine Zipper Transcription Factors; D001562:Benzimidazoles; D002219:Carbamates; D004268:DNA-Binding Proteins; D039621:Eukaryotic Initiation Factor-3; D005656:Fungal Proteins; D005659:Fungicides, Industrial; D000073718:Pancreatitis-Associated Proteins; C105096:Pap1 protein, S pombe; D010448:Peptide Initiation Factors; D039665:Prokaryotic Initiation Factor-3; D011518:Proto-Oncogene Proteins; C000612141:REG3A protein, human; D029702:Schizosaccharomyces pombe Proteins; C006698:carbendazim