title: Mechanism of transformation by v-ErbA: substitution for steroid hormone receptor function in self renewal induction.
abstract: V-ErbA, a mutated thyroid hormone receptor (TR) alpha cooperates with tyrosine kinase oncoproteins to induce fatal erythroleukemia in chicks. In vitro, v-ErbA employs a similar cooperation to induce sustained proliferation and arrest differentiation of committed erythroid progenitors. V-ErbA has been proposed to function as a dominant-negative c-ErbA/TR alpha, since it lacks an AF-2 transactivation domain and cannot be activated by hormone but retains the capacity to bind corepressors. However, v-ErbA fails to heterodimerize with the coreceptor RXR, exhibits an altered DNA binding specificity and fails to suppress the action of coexpressed TR alpha/c-ErbA in erythroblasts. In this paper, we identify a novel mechanism by which v-ErbA contributes to leukemogenesis. Recently, the glucocorticoid receptor (GR) was identified as a key regulator of proliferation and differentiation in normal erythroid progenitors. For this, the GR required to cooperate with endogenous receptor tyrosine kinases (c-Kit) and with the estrogen receptor (ER). Here, we demonstrate that v-ErbA can substitute for the ligand-activated GR and ER, inducing proliferation and arresting differentiation in the presence of specific GR and ER antagonists. Like the GR, v-ErbA required to cooperate with c-Kit for both proliferation induction and differentiation arrest, being devoid of biological activity in the absence of an active c-Kit. In self-renewing erythroblasts, v-ErbA not only repressed known v-ErbA target genes but also maintained high expression of c-myb. These biological activities of v-ErbA depended on distinct mutations in the DNA-binding domain. Additionally, v-ErbA acted as a partial, weak repressor of c-ErbA/TR alpha function in normal erythroblasts. It could be converted into a truly dominant-negative receptor by restoring its ability to heterodimerize with RXR.
authors.affiliation: Institute of Molecular Pathology, Vienna Biocenter, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Bauer
authors.forename: E
authors.initials: E
authors.lastname: Ulrich
authors.forename: M
authors.initials: M
authors.lastname: Andersson
authors.forename: H
authors.initials: H
authors.lastname: Beug
authors.forename: M
authors.initials: M
authors.lastname: von Lindern
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D002478:Cells, Cultured; D002642:Chick Embryo; D002645:Chickens; D004900:Erythroblasts; D005347:Fibroblasts; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors / Q000235:genetics; D007700:Kinetics; D018774:Oncogene Proteins v-erbA / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019000:Phosphotyrosine / Q000032:analysis; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism / Q000502:physiology; D020598:Proto-Oncogene Proteins c-myb; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D012190:Retroviridae / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014170:Transformation, Genetic
chemical_list: D018774:Oncogene Proteins v-erbA; D011518:Proto-Oncogene Proteins; D020598:Proto-Oncogene Proteins c-myb; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; D011988:Receptors, Thyroid Hormone; D015534:Trans-Activators; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit