MERIT Award Recipient: Martin L. Privalsky, Ph.D.
Mechanism of Action of the v-erb A Oncogene of AEV
Retroviruses integrate within the host cell genome during their life cycle and can inadvertently acquire snippets of host genes. Occasionally, these aberrant copies of host genes confer on the retrovirus the ability to cause cancer. The avian erythroblastosis virus (AEV), for example, has acquired segments of two host genes: one for a thyroid hormone receptor (denoted v-erb A), and one for the EGF-receptor (denoted v-erb B) that confer on this virus the ability to cause solid tumors and leukemias in AEV-infected animals. The researchers in the Privalsky laboratory seek to better understand how these oncogenic genes (oncogenes) function in cancer, how their function compares to that of their normal counterparts in the host organism, and the relationship of these phenomena to the molecular events that cause human cancers.
The Privalsky laboratory researchers are particularly interested in understanding how v-erb A contributes to the ability of AEV to cause leukemia. Thyroid hormone receptors in the normal host organism function as hormone-regulated transcription factors, and activate banks of specific target genes in response to thyroid hormone. The v-erb A gene is mutated relative to its normal gene counterpart, and the virus-encoded v-Erb A protein cannot activate, but instead constitutively represses target gene expression. As a result, v-Erb A can block the expression of genes that would normally be induced by thyroid hormone, and this "dominant-negative" function contributes to the actions of v-Erb A in leukemogenesis. Intriguingly, the DNA recognition properties of v-Erb A are also altered relative to those of its normal thyroid hormone receptor counterpart, and the ability of v-Erb A to cross-react with, and repress, retinoic acid receptor target genes also plays an important role in the oncogenic properties of AEV. Similar abnormalities in receptor function contribute to human endocrine disease and to human neoplasia, including acute promyelocytic leukemia, and investigations of these receptor-mediated human diseases represent additional projects in the Privalsky laboratory.
In summary, the research in the Privalsky laboratory seeks to elucidate the molecular basis of the altered transcriptional and DNA recognition properties of v-Erb A, and to use this information to better understand the functions of related hormone receptors. This work will help reveal how normal hormone receptors operate in human health, and how abnormal receptors contribute to human diseases.