We propose to better understand the mechanisms of action of the v-erb A oncogene, and to relate the role of v-erb A in viral neoplasia to events in normal differentiation and in human disease. V-erb A, an oncogene in the avian erythroblastosis retrovirus genome, participates in erythroid leukemogenesis and alters the growth properties of infected fibroblasts. V-erb A is a mutant, transduced copy of a normal cell gene (c-erb A) encoding a thyroid hormone receptor. Thyroid hormone receptors are ligand-regulated transcription factors, and belong to a larger family of nuclear receptors that play key roles in vertebrate development, homeostasis, and differentiation. Naturally occurring mutations in nuclear receptors have been implicated in important human endocrine and neoplastic diseases, including hepatocellular carcinoma, acute promyelocytic leukemia, renal clear cell carcinoma, and resistance to thyroid hormone syndrome. In many cases these mutant receptors, like v-Erb A, can act as dominant negatives. An important component of our research extends to understanding the molecular defects in these human diseases, and why different receptor mutations result in different diseases. We propose four specific aims to investigate these questions:
SPECIFIC AIM A. We will identify v-Erb A and PML-RARalpha target genes.
SPECIFIC AIM B. We will elucidate how v-Erb A represses target gene expression once bound to a target DMA SPECIFIC AIM C. We will elucidate how v-Erb A function is altered by other signal transduction pathways operative in the erythroleukemic cell SPECIFIC AIM D. We will use v-Erb A as a model to improve our understanding of the actions of the aberrant nuclear receptors involved in human disease.
to public health: This research will help establish how alterations in normal genes can lead to cancers and other diseases. It will also contribute to our understanding of how hormone receptors function in normal physiology and development.
|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|
|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|
|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, 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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