The action of the v-ErbA oncogene within the regulatory and structural networks of Xenopus laevis oocytes.
Thesis DisciplineCellular and Molecular Biology
Degree GrantorUniversity of Canterbury
Degree NameDoctor of Philosophy
Expression in Xenopus oocytes revealed differential modes of regulation of the constitutive trans-activation domains present in the thyroid hormone receptor (TR) and its oncogenic homolog v-ErbA. The nuclear environment of oocytes induced a constitutive trans-activation function in TR, but not v-ErbA, at hormone-inducible thyroid hormone response elements (TREs), which was further enhanced by thyroid hormone at a subset of TREs. In contrast, DNA-protein interactions at a response element which is induced by unliganded TR in mammalian cells mediated constitutive trans-activation by both TR and v-ErbA. These findings indicate that the responses of the ligand-independent trans-activation domains of TR and v-ErbA to cell-specific and TRE-mediated induction are not equivalent. Pre-injection of nuclear protein extract from anterior pituitary cells converted v-ErbA into a strong constitutive activator at a response element from the rat growth hormone gene. Thus, the dominant negative phenotype of v-ErbA can be abolished by direct or indirect interactions with tissue-specific proteins. The growth-promoting properties of the v-erbA oncogene have so far exclusively been linked to dominant repression of the anti-mitogenic roles of TR and retinoic acid receptor. Ultrastructural analysis revealed that, when expressed in Xenopus oocytes, v-ErbA induced early to intermediate meiotic changes occurring prior to chromosome condensation. The effects of v-ErbA on cell cycle reentry in oocytes were not mimicked by a dominant negative mutant of TR, suggesting that v-ErbA did not initiate meiosis by antagonizing endogenous TR. v-ErbA-induced meiosis occurred independently of the cAMP/MPF signal pathway, but required mRNA synthesis and translation. These findings suggest that v-ErbA mediated the release from G2 arrest by activating expression of a cell cycle inducer(s).