V-erb A, un oncogène qui stimule la différenciation des myoblastes aviaires.

Abstract

L'oncogène v-ErbA, présent dans le génome du virus de l'érythroblastose aviaire, augmente le potentiel prolifératif des fibroblastes embryonnaires de poulet et bloque la différenciation des érythroblastes. En outre, la coopération avec v-ErbB, le second oncogène présent dans le génome de ce virus, induit la transformation des fibroblastes. Ces propriétés ont été associées à la capacité de l'oncoprotéine v-ErbA de réprimer l'activité des récepteurs de la triiodothyronine (T3) et de l'acide rétinoïque. En particulier, la synthèse de v-ErbA s'oppose à l'inhibition par ces récepteurs de l'activité transcriptionnelle du complexe AP-l dans les cellules HeLa. Les travaux effectués sur les myoblastes aviaires, dont la différenciation est stimulée par la T3 et l'acide rétinoïque, montrent que, paradoxalement, l'oncoprotéine présente une forte activité myogénique. Elle ne se comporte pas en antagoniste efficace du récepteur de la T3, en partie en raison de l'absence du récepteur RXR pendant la période de prolifération de ces cellules. Ces observations démontrent l'existence d'une spécificité tissulaire de l'activité de l'oncoprotéine v-ErbA.

The avian erythroblastosis retrovirus (AEV)) induces erythroleukaemias and fibrosarcomas in chicken, and also transforms fibroblasts and bone marrow cells in vitro. The genome of AEV carries two oncogenes transduced from the chicken genome designated as v-ErbA and V-ErbB. The v-ErbB oncogene encodes a truncated version of the chicken EGF/TGFalpha receptor displaying a constitutive tyrosine-kinase activity. The v-ErbA oncogene encodes a mutated version of the nuclear T3 receptor cErbA alpha1, not able to significantly bind T3. This oncoprotein generally behaves as a constitutive repossessor of gene transactivation by T3 and retinoic acid (RA) activated receptors. In addition, it overcomes the inhibition of AP-1 activity by liganded retinoic acid (RAR) or thyroid hormone (T3R) receptors. In association to this antagonism, v-ErbA alters in vitro growth requirements of chicken embryo fibroblasts and blocks differentiation of normal avian erythrocyte progenitors. As in erythrocytic precursors, muscle cell differentiation is stimulated by T3 and RA. However, v-ErbA expression stimulates proliferation and strongly enhances avian myoblast differentiation. This myogenic activity is abrogated by mutation of serine 61, located at the basis of the first zinc finger of the v-ErbA DNA binding domain and involved in the recognition of specific nucleotidic sequences. This observation suggests that v-ErbA could affect the expression of a set of genes involved in the regulation of myoblast differentiation. In myoblasts, as in other cell types, v-ErbA efficiently represses RAR activity. However, AP-1/T3R interactions are not a v-ErbA target in avian myoblasts. In addition, v-ErbA inhibits the transcriptional activity of T3R/RXR heterodimers in these cells, but does not affect the T3R activity recorded in RXR absence during myoblast proliferation. Overall, the oncoprotein could only repress transcriptional activity of T3R after the induction of RXR expression occurring just before terminal differentiation, and does not alter AP-1 inhibition by T3. When v-ErbA expression does not obviously exceed T3R endogenous expression, the oncoprotein induces a hormone-independent stimulation of T3 pathways (inhibition of AP-1 activity and transcriptional activity). We suggest that this T3R/v-ErbA interaction could partly explain the oncoprotein myogenic influence. Last, as RXR expression in myoblasts restores the transcriptional v-ErbA/c-ErbA antagonism and abrogates the myogenic influence of the oncoprotein, it appears that the lack of RXR expression during myoblast proliferation could probably explain the muscle-specific activity of v-ErbA. In transgenic mice expressing v-ErbA a general decrease in the development of the animals is observed. However, muscle development is not obviously altered, suggesting that, in a general context of uuderdevelopment, muscle growth was privileged. Athough more complete studies focused on muscle development are needed in these animals, these in vivo data could be in agreement with the stimulation of myoblast proliferation and differentiation induced in vitro by v-ErbA expression. [References: 56]