A fission yeast homolog of Int-6, the mammalian oncoprotein and eIF3 subunit, induces drug resistance when overexpressed
A fission yeast homolog of Int-6, the mammalian oncoprotein and eIF3 subunit, induces drug resistance when overexpressed
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DOI：
10.1091/mbc.11.11.3993
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发表时间：
2000-11-01
影响因子：
3.3
通讯作者：
Norbury, C
中科院分区：
文献类型：
--
作者：
Crane, R;Craig, R;Norbury, C
通过筛选，以确定诱导多药耐药的基因时，过度表达，我们已经确定了一个裂殖酵母同源物的Int-6，一个组成部分的人翻译起始因子eIF 3。小鼠乳腺肿瘤病毒（MMTV）对小鼠Int-6基因的破坏与肿瘤发生有关，但其潜在机制尚不清楚。裂变酵母Int 6被证明与其他推定的eIF 3在体内的组成部分，并存在于与其纳入43 S翻译preinitiation复合物相一致的大小部分。Int 6过表达诱导的耐药依赖于AP-1转录因子Pap 1，并与Pap 1响应性mRNA丰度增加相关，但与Pap 1重新定位无关。缺乏int 6基因的裂变酵母细胞生长缓慢。这种生长迟缓可以通过表达裂殖酵母或人源的全长Int 6或通过也赋予耐药性的裂殖酵母蛋白的C末端片段来校正，但不能通过对应于MMT破坏的鼠等位基因的预测产物的截短的人Int-6蛋白来校正。因此，对裂变酵母的研究可能有助于解释在MMT诱导的乳腺肿瘤发生过程中Int-6功能受到干扰的方式。
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.