Myb-Ets Fusion Oncoprotein Inhibits Thyroid Hormone Receptor/c-ErbA and Retinoic Acid Receptor Functions: a Novel Mechanism of Action for Leukemogenic Transformation by E26 Avian Retrovirus

Abstract

The E26 and avian erythroblastosis virus (AEV) avian retroviruses induce acute leukemia in chickens. E26 can block both erythroid and myeloid differentiation at an early multipotent stage. Moreover, E26 can block erythroid differentiation at the erythroid burst-forming unit/erythroid CFU (BFU-E/CFU-E) stage, which also corresponds to the differentiation stage blocked by AEV. AEV carries two oncogenes, v-erbA and v-erbB, whereas E26 encodes a single 135-kDa Gag-Myb-Ets fusion oncoprotein. v-ErbA is responsible for the erythroid differentiation arrest through negative interferences with both the retinoic acid receptor (RAR) and the thyroid hormone receptor (T3R/c-ErbA). We investigated whether Myb-Ets could block erythroid differentiation in a manner similar to v-ErbA. We show here that Myb-Ets inhibits both RAR and c-ErbA activities on specific hormone response elements in transient-expression assays. Moreover, Myb-Ets abrogates the inactivation of transcription factor AP-1 by RAR and T3R, another feature shared with v-ErbA. Myb-Ets also antagonizes the biological response of erythrocytic progenitor cells to retinoic acid and T3. Analysis of a series of mutants of Myb-Ets reveals that the domains of the oncoprotein involved in these inhibitory activities are the same as those involved in oncogenic transformation of hematopoietic cells. These data demonstrate that the Myb-Ets oncoprotein shares properties with the v-ErbA oncoprotein and that inhibition of ligand-dependent RAR and c-ErbA functions by Myb-Ets is responsible for blocking the differentiation of hematopoietic progenitors.

Role of the different RAR isoforms in controlling the erythrocytic differentiation sequence. Interference with the v-erbA and p135gag-myb-ets nuclear oncogenes

“…The v-erbA oncoprotein inhibits RA-induced transcription from the PAL-0 but not from the DR-2 response element (Hermann et al, 1993). It does not inhibit DR-5 RARE in P19, COS-7 and MCF-7 cells (Barettino et al, 1993;Sharif and Privalsky, 1991) in contrast to HeLa cells (Rascle et al, 1996). In CV-1 cells the DR-5 RARE composed of two repeats of the AGGTCA motif is eciently repressed by v-erbA in contrast to the imperfect DR-5 made of the AGTTCA and GGTTCA motifs which is in agreement with the binding eciency of the oncoprotein to these elements .…”

“…In CV-1 cells the DR-5 RARE composed of two repeats of the AGGTCA motif is eciently repressed by v-erbA in contrast to the imperfect DR-5 made of the AGTTCA and GGTTCA motifs which is in agreement with the binding eciency of the oncoprotein to these elements . In HeLa cells transcription from the imperfect DR-5 is repressed by v-erbA like the whole promoter of the RARb gene which contains this speci®c RARE (Rascle et al, 1996). In some cases, a transcriptional activation by v-erbA has been reported (Sharif and Privalsky, 1992).…”

“…We had previously shown that no RARb gene expression was detected after all-trans-retinoic acid treatment in established cell lines transformed with E26, a retrovirus that expresses the p135 gag-myb-ets nuclear oncogene (Rascle et al, 1996). We therefore decided to verify if the expression of that oncogene would be sucient to block the RARb gene induction.…”

“…Fourth, both we (Rascle et al, 1996) and others (Sande et al, 1993) have described that no such induction was detected in, respectively, E26-and AEV-transformed cell lines.…”

Retinoid X receptor suppresses transformation by the v-myb oncogene

“…We and others recently described that the v-Myb and RAR proteins reciprocally modify each others' functions, thus they can be considered as mutual antagonists [41][42][43]69]. RAR␣ expressed in v-myb-transformed monoblasts suppressed transformation and permitted RA-dependent differentiation into macrophage-like cells [41].…”