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An essential yeast protein, encoded by duplicated genes TIF1 and TIF2 and homologous to the mammalian translation initiation factor eIF-4A, can suppress a mitochondrial missense mutation.

ABSTRACT: We describe the isolation and characterization of two previously undescribed genes, TIF1 and TIF2, from Saccharomyces cerevisiae. The protein-encoding sequences of the two genes are highly conserved, resulting in two completely identical proteins, whereas the flanking regions show no obvious homology. The two yeast proteins are highly similar to the translation initiation factor eIF-4A from mouse. Elevated gene dosage of TIF1 or TIF2 results in the suppression of a missense mutation in the mitochondrial oxi2 gene, which codes for subunit III of cytochrome-c oxidase, although the sequence of the Tif protein indicates its cytoplasmic localization. Inactivation of either gene by gene disruption has no effect on cell viability or on mitochondrial functions. However, simultaneous inactivation of both genes is lethal to the cell.

SUBMITTER: Linder P

PROVIDER: S-EPMC286897 | biostudies-other | 1989 Apr

REPOSITORIES: biostudies-other

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An essential yeast protein, encoded by duplicated genes TIF1 and TIF2 and homologous to the mammalian translation initiation factor eIF-4A, can suppress a mitochondrial missense mutation.

Linder P P Slonimski P P PP

Proceedings of the National Academy of Sciences of the United States of America 19890401 7

We describe the isolation and characterization of two previously undescribed genes, TIF1 and TIF2, from Saccharomyces cerevisiae. The protein-encoding sequences of the two genes are highly conserved, resulting in two completely identical proteins, whereas the flanking regions show no obvious homology. The two yeast proteins are highly similar to the translation initiation factor eIF-4A from mouse. Elevated gene dosage of TIF1 or TIF2 results in the suppression of a missense mutation in the mitoc ...[more]

PMID: 2648398

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Project description:Breast cancer stem cells (BCSCs) are intrinsically chemoresistant and capable of self-renewal. Following chemotherapy, patients can develop minimal residual disease due to BCSCs which can repopulate into a relapsed tumor. Therefore, it is imperative to co-target BCSCs along with the bulk tumor cells to achieve therapeutic success and prevent recurrence. So, it is vital to identify actionable molecular targets against both BCSCs and bulk tumor cells. Previous findings from our lab and others have demonstrated that inhibition of the emerging drug target eIF4A with Rocaglamide A (RocA) was efficacious against triple-negative breast cancer cells (TNBC). RocA specifically targets the pool of eIF4A bound to the oncogenic mRNAs that requires its helicase activity for their translation. This property enables specific targeting of tumor cells. The efficacy of RocA against BCSCs is unknown. In this study, we postulated that eIF4A could be a vulnerable node in BCSCs. In order to test this, we generated a paclitaxel-resistant TNBC cell line which demonstrated an elevated level of eIF4A along with increased levels of cancer stemness markers (ALDH activity and CD44), pluripotency transcription factors (SOX2, OCT4, and NANOG) and drug transporters (ABCB1, ABCG2, and ABCC1). Furthermore, genetic ablation of eIF4A resulted in reduced expression of ALDH1A1, pluripotency transcription factors and drug transporters. This pointed out that eIF4A is likely associated with selected set of proteins that are critical to BCSCs, and hence targeting eIF4A may eliminate BCSCs. Therefore, we isolated BCSCs from two TNBC cell lines: MDA-Bone-Un and SUM-159PT. Following RocA treatment, the self-renewal ability of the BCSCs was significantly reduced as determined by the efficiency of the formation of primary and secondary mammospheres. This was accompanied by a reduction in the levels of NANOG, OCT4, and drug transporters. Exposure to RocA also induced cell death of the BCSCs as evaluated by DRAQ7 and cell viability assays. RocA treatment induced apoptosis with increased levels of cleaved caspase-3. Overall, we identified that RocA is effective in targeting BCSCs, and eIF4A is an actionable molecular target in both BCSCs and bulk tumor cells. Therefore, anti-eIF4A inhibitors could potentially be combined synergistically with existing chemo-, radio- and/or immunotherapies.

Dataset Information

An essential yeast protein, encoded by duplicated genes TIF1 and TIF2 and homologous to the mammalian translation initiation factor eIF-4A, can suppress a mitochondrial missense mutation.

Publications

An essential yeast protein, encoded by duplicated genes TIF1 and TIF2 and homologous to the mammalian translation initiation factor eIF-4A, can suppress a mitochondrial missense mutation.

Similar Datasets

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