- Pediatric Hematology-Oncology
Medical Education: Stanford School of Medicine (1990) CA
Board Certification: American Board of Pediatrics, Hospice and Palliative Medicine (2010)
Board Certification: American Board of Pediatrics, Pediatric Hematology-Oncology (1996)
Fellowship: Lucile Packard Children's Hospital (1996) CA
Residency: Lucile Packard Children's Hospital (1993) CA
ORGANIZATION AND FUNCTION OF A DIOXIN-RESPONSIVE ENHANCER
JOURNAL OF BIOLOGICAL CHEMISTRY
1990; 265 (17): 9676-9681
The dioxin-responsive enhancer upstream of the CYP1A1 gene contains four copies of the recognition motif for the liganded Ah receptor. The results of deletion analyses, linker-scanning analyses, and the analysis of individual enhancer subdomains reveal that each copy of the motif contributes to the response of the enhancer to 2,3,7,8-tetrachlorodibenzo-p-dioxin. In the context of the dioxin-responsive enhancer, a GC box, representing the DNA binding site for Sp1 (or a related transcription factor), has no detectable intrinsic activity but enhances gene expression when linked to a recognition motif for the liganded Ah receptor, thereby producing a synergistic effect on enhancer function.
View details for Web of Science ID A1990DH14100020
View details for PubMedID 2161840
PROTEIN-DNA INTERACTIONS AT RECOGNITION SITES FOR THE DIOXIN-AH RECEPTOR COMPLEX
JOURNAL OF BIOLOGICAL CHEMISTRY
1989; 264 (28): 16478-16482
Gel retardation analyses reveal a cluster of six binding sites for the liganded Ah receptor within a 700-base pair DNA domain upstream of the mouse CYP1A1 gene. The nucleotide sequences of the binding sites define a consensus recognition motif for the liganded receptor. The consensus motif is not symmetric. Alteration of the consensus motif produces a decrease in the receptor-DNA interaction. The ligand receptor binds as a monomer to its recognition motif and preferentially binds to double-stranded DNA. These observations reveal apparent differences between 2,3,7,8-tetrachlorodibenzo-p-dioxin and steroid hormones in their respective mechanisms of action.
View details for Web of Science ID A1989AR64100024
View details for PubMedID 2550446
INDUCTION OF HEPATIC CYTOCHROME-P450 GENE-EXPRESSION BY 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN
MOLECULAR BIOLOGY & MEDICINE
1989; 6 (2): 169-178
The halogenated aromatic hydrocarbon 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) is a persistent, widespread, potentially toxic environmental contaminant, which is a potent inducer of aryl hydrocarbon hydroxylase activity in the liver and other tissues. TCDD induces hydroxylase activity by increasing the rate of transcription of the CYP1A1 gene. Activation of CYP1A1 transcription requires the binding of TCDD to an intracellular protein, the Ah receptor, followed by the binding of the liganded receptor to a dioxin-responsive enhancer that is located upstream from the CYP1A1 gene. The liganded receptor recognizes a specific DNA sequence, which is present in multiple copies within the enhancer. The receptor-enhancer interaction occurs within the major groove of the DNA helix. DNA methylation in vitro interferes with the receptor-enhancer interaction and, therefore, has the potential to inhibit the biological response to TCDD.
View details for Web of Science ID A1989CB47800010
View details for PubMedID 2693891
- REGULATION OF CYTOCHROME-P1-450 GENE-EXPRESSION IN MOUSE HEPATOMA-CELLS BY 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN DRUG METABOLISM REVIEWS 1989; 20 (2-4): 839-846
INDUCIBLE, RECEPTOR-DEPENDENT PROTEIN-DNA INTERACTIONS AT A DIOXIN-RESPONSIVE TRANSCRIPTIONAL ENHANCER
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
1988; 85 (8): 2528-2532
We have identified in mouse hepatoma cells a third cis-acting dioxin-responsive element (DRE) within the 5' flanking region of the cytochrome P1-450 gene, which is transcriptionally activated by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The DRE can activate a heterologous promoter and functions in either orientation; therefore, it has the properties of a transcriptional enhancer. The DRE fails to activate transcription in receptor-defective cells; therefore, it requires TCDD-receptor complexes for its function. By using a gel retardation assay, we show that nuclear extracts contain a protein that binds to the DRE in TCDD-inducible, receptor-dependent, and DNA sequence-specific fashion. The protein-DNA interaction occurs within 10 min of exposure of the cell to TCDD and does not require ongoing protein synthesis. Our results imply that the TCDD-receptor complex interacts specifically with the DRE and demonstrate a relationship between protein-DNA interaction in vitro and function in vivo. Our findings also suggest that the affinity of the TCDD-receptor complex for the DRE may be relatively high in comparison to analogous protein-DNA interactions at other inducible enhancers.
View details for Web of Science ID A1988N023400024
View details for PubMedID 2833743
2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN RECEPTORS REGULATE TRANSCRIPTION OF THE CYTOCHROME-P1-450 GENE
JOURNAL OF CELLULAR BIOCHEMISTRY
1987; 35 (2): 153-160
The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) dioxin, produces a diverse set of biological responses which, in some cases, reflects the altered expression of specific genes. An intracellular receptor protein binds TCDD saturably and with high affinity and mediates several of TCDD's biological effects. In mouse hepatoma cells, TCDD induces aryl hydrocarbon hydroxylase activity by activating the transcription of the cytochrome P1-450 gene. Studies of receptor-defective variant cells indicate that the activation of cytochrome P1-450 gene transcription requires functional TCDD receptors. Analysis of the DNA that flanks the 5'-end of the mouse cytochrome P1-450 gene reveals at least three control regions: a promoter, an inhibitory element, and a dioxin-responsive element (DRE). Therefore, expression of the cytochrome P1-450 gene represents a balance between negative and positive control. The DRE contains two discrete, non-overlapping DNA domains that respond to TCDD. Each TCDD-responsive domain acts independently of the other, each requires TCDD receptors for function, and each has the properties of a transcriptional enhancer. For example, the function of the DREs is relatively independent of both their location and their orientation with respect to the promoter. Together, the DREs and the TCDD-receptor complex constitute a dioxin-responsive enhancer system. Exposure of cells to TCDD results in the protection of a specific DNA domain from exonuclease digestion. This protection requires TCDD receptors. The protected domain maps to a DRE. This observation implies that the TCDD-receptor complex interacts with the DRE to activate the transcription of the cytochrome P1-450 gene.
View details for Web of Science ID A1987K545100007
View details for PubMedID 2828385