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 o verexpressed, we have identified a fission yeast homolog of Int-6, a compon ent of the human translation initiation factor eIF3. Disruption of the muri ne Int-6 gene by mouse mammary tumor virus (MMTV) has been implicated previ ously in tumorigenesis, although the underlying mechanism is not yet unders tood. Fission yeast Int6 was shown to interact with other presumptive compo nents of eIF3 in vivo, and was present in size fractions consistent with it s incorporation into a 43S translation preinitiation complex. Drug resistan ce induced by Int6 overexpression was dependent on the AP-1 transcription f actor Pap1, and was associated with increased abundance of Pap1-responsive mRNAs, but not with Pap1 relocalization. Fission yeast cells lacking the in t6 gene grew slowly. This growth retardation could be corrected by the expr ession of full length Int6 of fission yeast or human origin, or by a C-term inal fragment of the fission yeast protein that also conferred drug resista nce, but not by truncated human Int-6 proteins corresponding to the predict ed 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.