Disease relevance of EIF5A2

• EIF5A2 was discovered as a gene that is expressed in normal tissues, like testis (highly) and brain (at moderate levels) and in tumor-derived cells like colorectal adenocarcinoma. This is in sharp contrast to the ubiquitously expressed EIF5A1 gene [1].
• Overexperssion in tumor-derived cells correlates with gene copy number [2] [3].
• Populations of infertile and fertile men were screened for mutations in SPO11 and EIF5A2, two infertility candidate genes, but no correlation with male infertility was found [4].
• The oncogenic role of eIF5A-2 in the development of ovarian cancer and [5] colorectal cancer candidate was suggested early on [5]. The suggestion has been verified [6] [7] and to also correlate with the disease outcome in urothelial carcinoma [8] [9] and hepatocellular carinoma [10] [11].
• The corresponding mouse gene, Eif5a2 to be part an amplified region of chromosome 3, nearby Pik3ca [12], like in human ovarian cancers [3]. In the same study Eif5a1 was found to more heavily depend on XPO4 for nucleocytoplasmic export that Eif5a2. The otuhirs also found that nude mice injected with a vector expressiong Eif5a2, but not Eif5a1, triggered tumorogenesis [12]. The authors proposed eIF5A-2 as a target for therapeutic intervention in the 30 % of human breast cancers that have lost XPO4.

High impact information on EIF5A2

• A candidate oncogene (EIF5A2) encoding eukaryotic initiation factor 5A2 ( eIF5A-2), a member of eukaryotic initiation factor 5A subfamily, was been isolated from a frequently amplified region at 3q26 [5].
• Furthermore, antisense DNA against EIF5A2 could inhibit cell growth in ovarian cancer cell line UACC-1598 with amplification of EIF5A2 in form of double minutes [5].
• Cell growth rate in UACC-1598 was also inhibited when the expression level of EIF5A2 was decreased by the reduction of the copy number of double minutes [5].
• Several candidate oncogenes located on 3q have been proposed, e.g., PIK3CA, p63, and EIF5A2 [13].
• The proliferation-related function of eIF5A supports that EIF5A2 is a candidate oncogene related to the development of ovarian cancer [14].

Biological context of EIF5A2

• The two human genes EIF5A1 on chromosome 17 (p12-p13) and EIF5A2 on chromosome 3 (q25-q27) respectively, encode eIEF5A-1 (154 amino acids) and eIF5A-2 (153 amino acids) that are and 84 % idential and 94 % similar.
• EIF5A2 stretches over 17 kb and consists of five exons and four introns [1].
• Four EIF5A2 mRNAs (0.7, 1.6, 3.8, and 5.6 kb in length) share a 129-nt 5' UTR and a coding sequence for the 153-amino-acid eIF5A-2 protein, but possess four alternative 3' UTRs that arise through differential polyadenylation [1] [2].
• One EIF5A2-pseudogene is located on chromosome 15.
• Overexpression of eIF5A-2 mRNA in certain human cancer cells, in contrast to weak normal expression limited to human testis and brain, suggested EIF5A2 as a potential oncogene [15].
• The eIF5A-2 protein, like the the eIF5A-1 protein, is post-translationally modified with hypusine [16]. Hypusine is essential for its function to stimulate ribosomal peptidyltransfase activity.
• The eIF5A-proteins are mainly localized to the cytoplasm, and possess an N-terminal nuclear export signal [17]. Export is thought to be mediated by XPO4 [18].

Anatomical context of EIF5A2

• Amplification and overexpression of EIF5A2 was frequently detected in primary ovarian cancers and ovarian cancer cell lines [14].

Enzymatic interactions

• Lysine 50 is the target for hypusine modification. In the first step deoxyhypusine synthase, the encoded by DHPS, adds the aminobutyl part of spermidine to the 6-amine to form deoxyhypusine.
• N1-guanyl-N1,N7-diaminoheptane, or GC7, is an efficient inhibitor of DHPS [19].
• In the second step deoxyhypusine hydroxylase (deoxyhypusine mono-oxygenase) DOHH transfers one oxygen to the C-2 of the newly added aminobutly moiety.
• Iron chelators, such as mimosine, deferoxamine and ciclopirox are efficient inhibitors of DOHH [20] [21].
• Lysine 47 in eIF5A-1, and by implication also in eIF5A-2, is post-translationally acetylated, by a hitherto unknown acetylase [22].

Other interactions of EIF5A2

• While the exact binding site on the euokaryotic ribosome has been established, by inference with the bacterial homologue EFP, eIF5A proteins are likely to bind to E-site close to or even inserting the hypusine into the peptidyltransferase center [23].

References