Disease relevance of Eif3s6

• The translation initiation factor eIF3-p48 subunit is encoded by int-6, a site of frequent integration by the mouse mammary tumor virus genome [1].
• Fission yeast Int6 is not essential for global translation initiation, but deletion of int6(+) causes hypersensitivity to caffeine and affects spore formation [2].
• MMTV was integrated into Int-6 in a mammary hyperplastic outgrowth line, its tumors and metastases, and two independent mammary tumors arising in unrelated mice [3].
• Exclusion of Int-6 from PML nuclear bodies by binding to the HTLV-I Tax oncoprotein [4].
• These observations provide direct evidence that the Int6 mutations observed in MMTV-induced tumors and hyperplasia contribute to the malignant transformation of the mammary epithelial cells [5].

High impact information on Eif3s6

• Here, Int-6 was localized in the cell nucleus to give a speckled staining pattern superposed to that of the promyelocytic leukemia (PML) protein [4].
• In mice, the Int-6 gene can be converted into a putative dominant negative oncogene after retroviral insertion [4].
• Whereas the budding yeast genome does not encode a protein closely related to murine Int-6, fission yeast does encode an Int-6 ortholog, designated here Int6 [6].
• In line with this observation, the Wee1 tyrosine kinase that negatively controls Cdk1 was less efficiently inactivated during G2 in Int-6-depleted cells [7].
• These findings support the notion that the oncogenic properties associated with alteration of Int-6 originate from chromosomal instability [7].

Biological context of Eif3s6

• The Int-6 gene is ubiquitously expressed as a 1.4-kb RNA species in adult tissues and is detected beginning at day 8 of embryonic development [3].
• The nucleotide sequence of Int-6 is unrelated to any of the known genes in the GenBank database [3].
• In each tumor tested, this results in the expression of a truncated Int-6/long terminal repeat (LTR) chimeric RNA species which is terminated at a cryptic termination signal in the MMTV LTR [3].
• Comparisons between the Int6 genes of the inbred mouse laboratory strains and the wild mouse species Mus spretus and Mus mus musculus indicate that some pseudogenes were present before divergence of these species and others were acquired since their separation [8].
• In the mouse genome there are several other Int6-reactive restriction fragments that are located on mouse chromosomes 6, 11, 14, 17, and 18 [8].

Anatomical context of Eif3s6

• This latter observation is supported by immunoperoxidase analysis, which shows a strong staining anti-Int6 peptide in the perinuclear region of the HC11 mammary epithelial cell line, suggesting a possible localization in the Golgi apparatus [9].
• Further immunocytochemical studies in the mouse embryo show that Int6 expression is prevalent in migrating neural crest cells, in the notochord, and in condensing cartilage between 9.5 and 14.5 days of development [9].
• In this study, Int-6 is characterised as a 52 kDa protein that is localised within nuclear bodies in primary lymphocytes [10].
• Here, we show that reducing Int-6 expression by RNA interference in HeLa cells markedly alters mitosis progression [7].
• Stable expression of a truncated eIF3e in NIH 3T3 cells causes malignant transformation by four criteria: foci formation; anchorage independent growth; accelerated growth; and lack of contact inhibition [11].

Other interactions of Eif3s6

• The restricted expression of the protein within the Golgi apparatus and its strong conservation throughout evolution suggest that Int6 may perform an essential cellular function [9].
• Malignant transformation by the eukaryotic translation initiation factor 3 subunit p48 (eIF3e) [11].
• Reduced expression of INT-6/eIF3-p48 in human tumors [12].

Analytical, diagnostic and therapeutic context of Eif3s6

• Motivated by the involvement of Int-6 in transcriptional control, we investigated the effects of deleting PCI8 on the total mRNA expression profile by oligonucleotide microarray analysis and found reduced mRNA levels for a subset of heat shock proteins in the pci8Delta mutant [13].
• Colonies selected from agar exhibited high levels of mutated Int6sh and wild type Int6 RNA transcripts by RT-PCR and Northern blot analysis [5].

References