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

Abstract

Little is known as to how the nuclear oncogenes v-erbA and p135gag-myb-ets do transform cells. The elucidation of their molecular mechanisms of action requires the identi®cation of relevant target genes. We analysed the possibility for the RARb gene to represent such a target gene. We ®rst show that the RARb gene induction is a speci®c and direct process, requiring the continous presence of retinoids and under the control of the RARa isoform exclusively. We then show that the expression of either the v-erbA or the p135 gag-myb-ets oncogene is not sucient to block the RARb gene induction. We con®rmed the loss of RARb gene response in certain cell lines but we discarded the possibility that this loss might represent a necessary step for cell lines immortalization. We further show that the RARa isoform activation is necessary and sucient to induce the growth inhibition and the dierentiation stimulation characteristic for the commitment-inducing ability of retinoids in chicken erythrocytic progenitor cells. We therefore propose a model showing that RARa but not RARb is the key mediator for commitment to dierentiation and that it should control two dierent set of genes whose expression is dierentially aected by the verbA and the p135 gag-myb-ets oncogenes.

A Novel Way to Induce Erythroid Progenitor Self Renewal: Cooperation of c-Kit with the Erythropoietin Receptor

“…In contrast, SCF/TGF␣ progenitors showed little sensitivity to T3, but showed a weak response to RAR/RXR ligand. Our results agree with those of Gandrillon and Samarut (1998), showing that both v-ErbBtransformed and normal, c-ErbB expressing erythroblasts respond to RAR␣-specific ligands.…”

“…Proliferation during differentiation induction was hardly affected and only a minor upregulation of hemoglobin levels was seen ( Figure 5E and data not shown). RO40-6973 weakly inhibited proliferation induction and upregulated hemoglobin levels, in line with results by others (Gandrillon and Samarut, 1998).…”

“…In primary avian bone marrow cells, T3 and all-trans/9-cis retinoic acid mixtures enhanced erythroid differentiation. Furthermore, c-ErbB-expressing erythroblasts even required T3 and/or RAR ligands for complete differentiation (Gandrillon and Samarut, 1998;Gandrillon et al, 1994;Schroeder et al, 1992b). Using T3 as well as synthetic, stable ligands for both RAR␣ and its heterodimerization partner RXR, in combination with sera devoid of T3 and retinoids, we show that EpoR progenitors are unresponsive to RAR/RXR ligands, while T3 strongly inhibited their proliferation and accelerated their differentiation.…”

“…Besides the cytokines and steroid hormones tested above, thyroid hormone and/or retinoids may also play an important role in regulating erythropoiesis (Gandrillon and Samarut, 1998;Gandrillon et al, 1994;Schroeder et al, 1992a, b). We therefore asked how activation of the thyroid hormone receptor (TR␣/c-ErbA), activation of the retinoic acid receptor ␣ (RAR␣) or complete withdrawal of ligands for both the TR␣/c-ErbA and/or RAR␣ would affect the differentiation of EpoR progenitors.…”

Extracting Signature Motifs from Promoter Sets of Differentially Expressed Genes

“…Some other patterns are also of interest, and can be expected knowing the molecular action of v-ErbA. Indeed this oncogene is known to interfere with nuclear receptors, including RXR and GR [36]. Since v-ErbA is known to block the erythroid differentiation process [31], it is also expected to see some overlap between v-ErbA target genes and genes containing binding sites for the erythroid specific TF GATA-1 [37].…”