Role of the different RAR isoforms in controlling the erythrocytic differentiation sequence.: Interference with the v-erbA and p135gap-myb-ets nuclear oncogenes

Little is known as to how the nuclear oncogenes v-erbA and p135(gag-myb-ets) do transform cells. The elucidation of their molecular mechanisms of action requires the identification of relevant target genes. We analysed the possibility for the RAR beta gene to represent such a target gene. We first show that the RAR beta gene induction is a specific and direct process, requiring the continous presence of retinoids and under the control of the RAR alpha isoform exclusively. We then show that the expression of either the v-erbA or the p135(gag-myb-ets) oncogene is not sufficient to block the RAR beta gene induction. We confirmed the loss of RARE gene response in certain cell lines but we discarded the possibility that this lass might represent a necessary step for cell lines immortalization. We further show that the RAR alpha isoform activation is necessary and sufficient to induce the growth inhibition and the differentiation stimulation characteristic for the commitment-inducing ability of retinoids in chicken erythrocytic progenitor cells. We therefore propose a model showing that RAR alpha but not RAR beta is the key mediator for commitment to differentiation and that it should control two different set of genes whose expression is differentially affected by the v-erbA and the p135(gag-myb-ets) oncogenes.