The v-erbA oncogene requires cooperation with tyrosine kinases to arrest erythroid differentiation induced by ligand-activated endogenous c-erbA and retinoic acid receptor.
The v-erbA oncogene, a mutated version of the thyroid hormone receptor alpha (c-erbA/TR-alpha), cooperates with tyrosine kinase oncogenes in erythroblast transformation. Here we show that the ligand-activated, endogenous retinoic acid receptor (RAR-alpha), in cooperation with c-erbA/TR-alpha, efficiently reverses the transforming effect of kinase oncogenes, overcoming oncogene-induced self-renewal by triggering terminal differentiation of the transformed cells into healthy erythrocytes. This differentiation induction was accompanied by up-regulation of erythrocyte gene expression. Similarly, RAR-alpha and over-expressed exogenous c-erbA/TR-alpha efficiently abolished the differentiation arrest caused by v-erbA, while the low levels of endogenous TR-alpha had no effect. In contrast, transformation by v-erbA plus a kinase oncogene was not affected at all by ligand-activated endogenous or over-expressed exogenous TR-alpha and RAR-alpha. These results suggest that oncogene cooperation is required to protect leukemic erythroblasts from differentiation induction via endogenous, nuclear hormone receptors. Endogenous c-erbA/TR-alpha and RAR-alpha apparently cooperated in abolishing erythroblast self-renewal and inducing differentiation, since the respective ligands acted in a synergistic fashion, and overexpressed, non-ligand-bound c-erbA/TR-alpha suppressed endogenous RAR-alpha function in differentiation induction. Genetic evidence is presented that this functional cooperation requires the receptor dimerization domain, suggesting that TR-alpha/RAR-alpha heterodimers play a role in regulation of erythroid differentiation.
Institute of Molecular Pathology, Vienna, Austria.
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Schroeder
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Gibson
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Beug
D001798:Blood Proteins / Q000235:genetics; D002352:Carrier Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D004920:Erythropoiesis; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D018774:Oncogene Proteins v-erbA; D009857:Oncogenes; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone / Q000378:metabolism*; D015682:Retroviridae Proteins, Oncogenic / Q000502:physiology*; D014158:Transcription, Genetic; D014212:Tretinoin / Q000494:pharmacology; D014284:Triiodothyronine / Q000494:pharmacology
D001798:Blood Proteins; D002352:Carrier Proteins; D008024:Ligands; D018774:Oncogene Proteins v-erbA; D011518:Proto-Oncogene Proteins; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D015682:Retroviridae Proteins, Oncogenic; D014284:Triiodothyronine; D014212:Tretinoin; D011505:Protein-Tyrosine Kinases