Role Of Ets In Cancer And Disease

The oncogene v-ETS was originally discovered as a fused component of a chimeric genome in an avian leukosis virus, E26 (a replication-defective retrovirus that arose by transducing portions of two chicken cellular proto-oncogenes, myb and ETS1. The E26 oncogene transforms fibroblasts, myeloblasts, and ery-throblasts in vitro and causes mixed erythroid-myeloid and lymphoid leukemia in vivo [3,4],

Malignant transformation by leukemia retroviruses can also result from proviral integration upstream from specific cellular proto-oncogenes, activating gene expression. Activation of Spi-1 (PU.l) has been observed in a collection of murine erythroblastic tumors induced by spleen focus forming virus (SFFV). In rat thymomas induced by the Moloney strain of the Murine leukemia virus (Mo-MuLV), it has been found that proviral insertion events occurred at common integration loci thought to be associated with tumor progression, termed Tpl-1. These sites have now been shown to result in the rearrangement or activated expression of the ETS1 gene. Three different proviral

ETS1 (8) ETS2 [8] ERG2 [9] ELK1 [to] SPI1 (PU.l) in) ERGB/FLI1 [12,13] SAPla [14] ELFI [is] SPIB [16] E4TF1-60 (GABPa) [17] E1AF (PEA3) [18] PE1 [19] ERM [20] TEL [2i] SAP2 (NET/ERP) [22] ERF [23] ET VI [24,25] NERF2 [26] MEF [27]

PNT Domain

ETS Domain

ETS Domain

Fig. 1. The human ETS gene family. Schematic diagram of the human ETS proteins. Uppercase letters (A, B, C and R) define hypothetical ETS domains. The ETS domain is indicated by the black box. The conserved PNT (pointed) domain is shown as a stippled box.

insertions near the FLI1 gene lead to hematopoietic oncogenesis. The erythroleukemias induced by Friend-MuLV activate the FLI1 locus. Similarly, primitive stem cell tumors with characteristics of early hematopoietic cells and non-T, non-B lymphomas are induced by integration of the 10A1 isolate of MuLV or the Cas-Br viruses, respectively, near the FLI1 locus [4, 6],

Tumor cell formation also results from the translocation-associated production of FLI1 chimeric proteins as has been shown for Ewing's sarcoma (EWS), a childhood bone tumor, and related peripheral neuroectodermal tumors (PNET). In this instance, the FLI1 gene is translocated from its normal llq24 position to chromosome 22, which generates the formation of chimeric transcripts resulting in fusing the amino terminal region of the EWS gene to the car-boxy 1 terminal DNA-binding domain of the FLI1 gene. The chimeric fusion protein lacks the putative RNA-binding domain of EWS and one of the transac-tivation domains of the FLI1 gene product [3, 4, 6]. Structure-function analyses reveal that both the EWS and FLI1 regions of the EWS/FLI1 chimeric protein are particularly important for transforming activity in NIH3T3 cells. Three additional Ewing's sarcoma translocations have been described [t(21;22), t(7;22), t(2;22)] that result in chimeric proteins between EWS and three other ETS proteins, ERG, ETV1 and FEV, respectively [3,4,6, 33]. These fusion proteins may be unable to modulate ETS-targeted genes appropriately. Other targeted gene products might be activated by the unscheduled (and therefore inappropriate) specific interaction with the EWS binding domain. These actions could trigger autonomous growth of these tumor cells. In summary, whether by activation through retroviral transduction of cellular sequences, retroviral promoter integration or by chromosomal translocation, dysregu-lation of ETS has been shown to result in carcinogenic transformation.

5. EXPRESSION OF ETS1, ETS2 AND FLI1 GENES DURING NORMAL DEVELOPMENT

The ETS2 gene is expressed in most cell types, whereas ETS1 and FLI1 gene expression are tissue specific [3-6]. Expression of these genes in multiple tissues during embryonic development suggests that these genes may be required for multiple functions during critical stages of organogenesis. ETS1 expression is detected at around 8 days post conception (dpc). During embryogenesis, ETS1 expression is detected in lymphoid tissues, as well as several other organ systems (mostly in cells of mesodermal origin). ETS 1 gene expression in the thymus begins to appear two days before birth, coinciding with the appearance of mature (single positive) thymocytes. Expression of ETS1 is restricted primarily to lymphoid cells after birth. In contrast, ETS2 expression is more ubiquitous. While ETS2 expression is distinctly different from that of ETS1 during embryonic development and in the adult, FLI1 expression is similar to ETS1. Expression patterns during embryogenesis suggest that FLU may function in the development of mesodermal, endothelial and hematopoietic cells as well as in cells that are derived from the neural crest and in migrating neural crest cells. During later development, the overall expression levels decrease, with high levels remaining in newly formed mesenchymal cells. Expression observed in the spleen and thymus during development continues after birth. These studies are consistent with the hypothesis that FLI1 has a role in mesoderm formation and in the development of endothelial and hematopoietic lineages [5, 6].

The ETS-1 gene is expressed at higher levels in quiescent T cells and its expression decreases to very low levels after activation. The repression of ETS-1 gene expression requires both activation of protein kinase C and elevation of intracellular Ca2+ ions, and is dependent on de novo protein synthesis. While a similar pattern is observed for FLI1 gene expression, ETS2 expression is increased during T-cell activation [7].

6. EXPRESSION OF ETS1, ETS2, ERGB/FLI1 GENES IN LYMPHOCYTES FROM SLE PATIENTS

We have examined the expression of ETS1, ETS2 and ERGB/FLI1 genes in human PBMC samples from SLE patients and compared them with those from healthy individuals. A representative sample of Reverse Transcription-Polymerase Chain Reaction results from very active (samples 1 and 2), active (samples 3, 4 and 5), inactive SLE patients (samples 6 and 7), along with healthy individuals (sample 8) are shown in Fig. 2. Although ETS1 gene expression is 2-fold higher in SLE, its expression is independent of disease activity. However, both ERGB/FLI1 and ETS2 gene expression changed with the disease activity. ERGB/FLI1 gene expression is about 7-fold higher in very active SLE samples compared to its expression in healthy individuals. On the other hand, ETS2 gene expression is about 3-fold higher in very active SLE samples than in healthy individuals. We did not find any correlation of ETS 1, ERGB/FLI 1 and ETS2 gene expression between the duration of the disease, the clinical characteristics, the laboratory characteristics or the therapy.

7. EXPRESSION OF ETS1, ETS2, ERGB/FLI1 IN LYMPHOCYTES FROM AUTOIMMUNE PRONE MICE

New Zealand Black (NZB)/New Zealand White (NZW) provides a good model system because F1 hybrids of NZB with NZW develop autoimmune disease having characteristic phenotypes similar to that seen in human SLE. We studied ETS1, ETS2, ERGB/FLI 1 gene expression in thymocytes, splenic B and T cells from NZW, FI hybrids (NZB xNZW), as well as

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