Role of the different RAR isoforms in controlling the erythrocytic differentiation sequence. Interference with the v-erbA and p135gag-myb-ets nuclear oncogenes.
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 identification of relevant target genes. We analysed the possibility for the RARbeta gene to represent such a target gene. We first show that the RARbeta gene induction is a specific and direct process, requiring the continuous presence of retinoids and under the control of the RARalpha isoform exclusively. We then show that the expression of either the v-erbA or the p135gag-myb-ets oncogene is not sufficient to block the RARbeta gene induction. We confirmed the loss of RARbeta 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 RARalpha 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 RARalpha but not RARbeta 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 p135gag-myb-ets oncogenes.
Gandrillon
O
O
Départment de biologie moléculaire et cellulaire, Ecole normale supérieure de Lyon, France.
Samarut
J
J
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002645:Chickens; D004912:Erythrocytes / Q000166:cytology* / Q000502:physiology; D005786:Gene Expression Regulation; D015683:Gene Products, gag / Q000235:genetics*; D018776:Genes, erbA / Q000502:physiology*; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology; D007536:Isomerism; D018774:Oncogene Proteins v-erbA / Q000096:biosynthesis / Q000502:physiology; D009857:Oncogenes / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000072482:Retinoic Acid Receptor alpha; D015533:Transcriptional Activation
D015683:Gene Products, gag; D018774:Oncogene Proteins v-erbA; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; C082925:retinoic acid receptor beta