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Department of Molecular Medicine
 

Chatterjee Bandana  Chatterjee,  Ph.D.

Professor

Profile and Contact Information | Research | Laboratory

RESEARCH

 

Research Program

Our studies focus on two areas of nuclear receptor function: 1) the androgen receptor regulation of target gene expression and prostate cancer development; and 2) the orphan nuclear receptor regulation of the phase II pathway to steroid and drug metabolism.

1. Androgen Receptor, Gene Regulation and Prostate Cancer.
The androgen receptor (AR) is a ligand-regulated transcription factor and a member of the family of nuclear receptors that are activated in response to the signaling from lipophilic, small-molecule hormones and metabolites. Upon binding to its hormonal ligand, i.e. androgen, the AR is imported to the nucleus where, in collaboration with chromatin remodeling complexes, histone modifying complexes and various coregulatory factors and mediators, the receptor regulates target gene transcription. The proteins and enzymes encoded by androgen-regulated genes render major influences on numerous physiological processes including spermatogenesis, male sexual development, skeletal growth, muscle mass development and cognitive function. With chronic overexposure to androgen, however, the prostate and several other androgen target organs could become susceptible to aberrant cell growth and proliferation, leading to tumorigenesis. Our work aims to understand the molecular mechanism that underlies altered target gene expression in response to androgen receptor (AR)/androgen signaling and how this change contributes to the prostate cancer development. One major recent effort in the laboratory has been to identify and characterize the transcription factors that coordinate the age-dependent regulation of AR. In earlier work we had identified a novel age-dependent factor (ADF), which is a positive regulator of AR gene transcription. We showed that the ADF activity in rodents declines steadily to a non-detectable level at late senescence. We have now purified ADF and cloned its cDNA. Current work involves a detailed study of the cooperative interactions between ADF and other coregulators to modulate AR gene expression. The coregulatory factors being examined include chromatin remodeling complexes; histone-modifying acetylases and methyl transferases; the p160 coactivators and the corepressors NcoR and SMRT. Beyond the molecular studies, the role of ADF dependent AR function in the histopathology of the mouse prostate during aging is being investigated. A second project is to examine the functional interactions between AR and the vitamin D receptor (VDR) in the regulation of prostate cancer cell growth. Vitamin D is known to confer growth inhibition to prostate cancer cells. The mechanism of this growth inhibition is being examined in a cell culture model. Additionally, we have created a hybrid mouse model in which prostate targeted overexpression of the androgen receptor in mice occurs in a VDR-inactivated background. These mice exhibit focal neoplasia in the prostate. Our current focus is to characterize the prostates from these mice for tumor development and for gene expression profiles.

2. Orphan nuclear receptors in the regulation of steroid and drug metabolism.
The role of orphan nuclear receptors in the phase II metabolism of endogenous steroids and therapeutic drugs is a second focus in this laboratory. In particular, we are exploring the nuclear receptor regulation of enzymatic sulfonation mediated by a specific member of the sulfotransferase family, namely SULT2A1, which is a steroid and bile acid sulfotransferase. SULT2A1 substrates include several hydroxysteroids (DHEA, testosterone, dihydrotestosterone, estrogen and pregnenolone), the amphipathic sterols (primary and secondary bile acids) and numerous clinically useful drugs (among others, the antiestrogenic breast cancer drug hydroxytamoxifen; and the anti-inflammatory drug budenoside, a synthetic glucocorticoid). Our work has shown that SULT2A1 regulation is intricately linked to the metabolic circuitry that feeds into steroid/drug/xenobiotic metabolism. SULT2A1 expression is high in the liver, intestine and adrenal cortex and the gene is markedly up regulated during aging. We have shown that the bile acid receptor (FXR) and the xenobiotic receptors (PXR and CAR) are potent inducers of SULT2A1, while the androgen receptor (AR) is a negative regulator of this gene. FXR, PXR and CAR are members of the nuclear receptor superfamily, mediating bile acid signaling (FXR), and xenobiotic signaling (PXR and CAR). Using SULT2A as a model, we are studying the molecular mechanisms for target gene regulation by endobiotic (steroids, cholesterol metabolites) and xenobiotic compounds. Specifically, studies aim to characterize the functional interplay of chromatin remodeling complexes and coregulatory proteins with these nuclear receptors in regulating SULT2A gene transcription in primary hepatocytes by hormones and metabolites. Investigation is also under way to characterize the changes in this regulation during aging, caused by an altered endocrine and metabolic milieu.

Despite the usefulness of the SULT2A1 activity in the detoxification/clearance of drugs and endogenous steroids, in a yin-yang response, its overexpression in the enterohepatic tissues is potentially carcinogenic. SULT2A1 sulfonates, and thereby activates polycyclic aromatic hydrocarbons (PAH) to DNA-reactive carcinogens. PAHs are the common constituents of tobacco smoke, industrial wastes and organic foods cooked at high temperature. Activated PAH forms bulky, covalent adducts to DNA bases. These lesions, if not repaired, would have the potential to cause mutations in the genomic DNA that may trigger tumorigenesis, thus contributing to the development of liver cancer. Using a transgenic approach, we are analyzing the role of SULT2A1 in the formation of PAH-mediated DNA damage with a resulting impact on the growth and proliferation of liver cells.

 

Selected Publications

  1. Echchgadda I, Kota S, Dela Cruz I, Sabbah A, Chang T, Harnack R, Mgbemena V, Chatterjee B, and Bose S: Anticancer oncolytic activity of respiratory syncitial virus. Cancer Gene Ther.doi/10.1038/cgt.2009.34, 15th May, 2009.
  2. Shi L, Ko S, Kim S, Echchgadda I, Oh TS, Song CS, Chatterjee B: Loss of androgen receptor in aging and oxidative stress through the Myb protooncoprotein-regulated reciprocal chromatin dynamics of p53 and poly(ADP-ribose) polymerase PARP-1. J Biol Chem 283: 36474-85, (2008). Epub 2008 Oct. 21.
  3. KoS, Shi L, Kim SY, Song CS, Chatterjee B: Interplay of nuclear factor-kappaB and B-myb in the negative regulation of androgen receptor expression by tumor necrosis factor alpha. Mol Endocrinol. 22: 273-86, (2008).
  4. Echchgadda I, Song CS, Oh T, Ahmed M, De La Cruz IJ, and Chatterjee B: The xenobiotic-sensing nuclear receptors pregnane X receptor, constitutive androstane receptor, and orphan nuclear receptor hepatocyte nuclear factor 4alpha in the regulation of human steroid-/bile acid-sulfotransferase. Mol Endocrinol. 21: 2099-111, (2007).
  5. Seo YK, Chung YT, Kim S, Echchgadda I, Song CS, and Chatterjee B: Xenobiotic- and vitamin D-responsive induction of the steroid/bile acid-sulfotransferase Sult2A1 in young and old mice: the role of a gene enhancer in the liver chromatin. Gene 386: 218-23, 2007.
  6. Song CS, Echchgadda I, Seo YK, Oh T, Kim S, Kim SA, Cho S, Shi L, and Chatterjee B: An essential role of the CAAT/enhancer binding protein-alpha in the vitamin D-induced expression of the human steroid/bile acid-sulfotransferase (SULT2A1). Mol Endocrinol. 20: 795-808, 2006.
  7. Chatterjee B, Echchgadda I, and Song CS: Vitamin D receptor regulation of the steroid/bile acid sulfotransferase SULT2A1. Methods Enzymol., “Phase II: Conjugation Enzymes, Glutathione Transferases and Transport Systems." 400: 165-91, 2005.
  8. Echchgadda I, Song CS, Roy AK, and Chatterjee B: Dehydroepiandrosterone sulfotransferase is a target for transcriptional induction by the vitamin D receptor. Mol Pharmacol. 65: 720-9, 2004.
  9. Zhang L, Charron M, Wright WW, Chatterjee B, Song CS, Roy AK, and Brown TR: Nuclear factor-kappaB activates transcription of the androgen receptor gene in Sertoli cells isolated from testes of adult rats. Endocrinology 145 : 781-9, 2004.
  10. Chatterjee B: The role of the androgen receptor in the development of prostatic hyperplasia and prostate cancer. Mol Cell Biochem. 253: 89-101, 2003.
  11. Rivera OJ, Song CS, Centonze VE, Lechleiter JD, Chatterjee B,and Roy AK: Role of the promyelocytic leukemia body in the dynamic interaction between the androgen receptor and steroid receptor coactivator-1 in living cells. Mol Endocrinol. 17: 128-40, 2003 (cover article).
  12. Song CS, Echchgadda I, Baek BS, Ahn SC, Oh T, Roy AK, and Chatterjee B: Dehydroepiandrosterone sulfotransferase gene induction by bile acid activated farnesoid X receptor. J Biol Chem. 276: 42549-56, 2001.
  13. Tyagi RK, Lavrovsky Y, Ahn SC, Song CS, Chatterjee B, and Roy AK: Dynamics of intracellular movement and nucleocytoplasmic recycling of the ligand-activated androgen receptor in living cells. Mol Endocrinol. 14: 1162-74, 2000 (cover article).
  14. Chen S, Song CS, Lavrovsky Y, Bi B, Vellanoweth R, Chatterjee B, and Roy AK: Catalytic cleavage of the androgen receptor messenger RNA and functional inhibition of androgen receptor activity by a hammerhead ribozyme. Mol Endocrinol. 12: 1558-66, 1998 (cover article).
  15. Song CS, Jung MH, Kim SC, Hassan T, Roy AK, and Chatterjee B: Tissue-specific and androgen-repressible regulation of the rat dehydroepiandrosterone sulfotransferase gene promoter. J Biol Chem. 273: 21856-66, 1998.

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