The v-erbA oncogene of avian erythroblastosis virus is an aberrant copy of a gene for a thyroid hormone receptor. V-erbA can act as a transcriptional repressor, inhibiting expression of genes normally activated by thyroid hormone receptors. Therefore, v-erbA represents a novel class of oncogene, acting in cancer as a dominant negative allele.Dominant negative mutants of nuclear hormone receptors also play important roles in human endocrine and neoplastic diseases. The main objective of this proposal is to understand the mechanism of action of the v-erbA oncogene, and to relate its role in viral neoplasia to event in normal differentiation and in human disease. A. The targets of v-erbA action in the neoplastic cell will be identified. The following questions will be addressed: 1) What is the optimal DNA binding site for the v-erbA protein? 2) What role does the altered DNA binding specificity of v-erbA play in the neoplastic phenotype?3) What genes are actually regulated by the v-erbA protein in the erythroleukemic cell? B. The molecular basis for the altered DNA binding specificity of the v-erbA protein will be elucidated. C. The interaction of v- and c- erbA proteins with other important regulatory polypeptides will be investigated.In particular: 1) What is the molecular basis behind the different interaction of the v- and c-erbA proteins with one another and with RXRs? 2) What other regulatory factors interact with v- and c-erbA proteins to influence their functions? D. The v-erbA protein will be used as a probe to elucidate the role of retinoic X receptors in Xenopus and murine development.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Method to Extend Research in Time (MERIT) Award (R37)
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Virology Study Section (VR)
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University of California Davis
Schools of Medicine
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Rosen, Meghan D; Chan, Ivan H; Privalsky, Martin L (2011) Mutant thyroid hormone receptors (TRs) isolated from distinct cancer types display distinct target gene specificities: a unique regulatory repertoire associated with two renal clear cell carcinomas. Mol Endocrinol 25:1311-25
Chan, Ivan H; Privalsky, Martin L (2010) A conserved lysine in the thyroid hormone receptor-alpha1 DNA-binding domain, mutated in hepatocellular carcinoma, serves as a sensor for transcriptional regulation. Mol Cancer Res 8:15-23
Rosen, Meghan D; Privalsky, Martin L (2009) Thyroid hormone receptor mutations found in renal clear cell carcinomas alter corepressor release and reveal helix 12 as key determinant of corepressor specificity. Mol Endocrinol 23:1183-92
Chan, Ivan H; Privalsky, Martin L (2009) Isoform-specific transcriptional activity of overlapping target genes that respond to thyroid hormone receptors alpha1 and beta1. Mol Endocrinol 23:1758-75
Chan, I H; Privalsky, M L (2009) Thyroid hormone receptor mutants implicated in human hepatocellular carcinoma display an altered target gene repertoire. Oncogene 28:4162-74
Chan, I H; Privalsky, M L (2006) Thyroid hormone receptors mutated in liver cancer function as distorted antimorphs. Oncogene 25:3576-88
Lee, Sangho; Privalsky, Martin L (2005) Heterodimers of retinoic acid receptors and thyroid hormone receptors display unique combinatorial regulatory properties. Mol Endocrinol 19:863-78
Lee, Sangho; Privalsky, Martin L (2005) Multiple mutations contribute to repression by the v-Erb A oncoprotein. Oncogene 24:6737-52
Hayakawa, Fumihiko; Privalsky, Martin L (2004) Phosphorylation of PML by mitogen-activated protein kinases plays a key role in arsenic trioxide-mediated apoptosis. Cancer Cell 5:389-401
Yang, Z; Privalsky, M L (2001) Isoform-specific transcriptional regulation by thyroid hormone receptors: hormone-independent activation operates through a steroid receptor mode of co-activator interaction. Mol Endocrinol 15:1170-85

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