David J Shapiro

djshapir@illinois.edu

314d Roger Adams Lab
Office: (217) 333-1788
Lab: (217) 244-0207
Fax: (217) 244-5858

Mail to: Department of Biochemistry
419 Roger Adams Lab.
University of Illinois
600 S. Mathews Avenue
Urbana, IL 61801
Lab Page

David J Shapiro

Professor of Biochemistry

Research Topics

Chromatin Structure, Drug Discovery, Endocrinology, Protein-Nucleic Acid Interactions, Receptor Biochemistry, Regulation of Gene Expression, Signal Transduction

Education

B.S. 1967 Brooklyn College
Ph.D. 1972 Purdue University
Postdoc. 1972-1973 Stanford University Medical School, 1973-1974 Stanford University
1985 - 1986 Guggenheim Fellow, Center for Cancer Research MIT

Identification and use of small molecule biomodulators as novel anticancer drugs and probes for new regulatory pathways

Small molecule biomodulators for studying and treating cancer

Our previous research focused on mechanisms of steroid receptor regulated transcription and posttranscriptional control of mRNA degradation. We used these skills to develop powerful high throughput screening platforms for identifying small molecule modulators of steroid hormone receptor and mRNA binding protein action.

Estrogen and androgen receptor action in cancer

Steroid hormones, such as estrogens, act by binding to specific receptor proteins called steroid/nuclear receptors. In the nucleus, these receptors regulate gene expression. In the cytosol, they regulate signaling pathways. The estrogen and androgen (testosterone) receptors (ER) and (AR) stimulate cell proliferation. Estrogens, acting through the ER, are implicated in the growth and metastases of breast, ovarian, endometrial and lung cancer. Testosterone, acting through the AR, plays a key role in prostate cancer. Over time tumors become resistant to current therapies targeting estrogen action, and tumor growth resumes with few therapeutic options. We identify and develop new small molecule inhibitors that are effective against tumors resistant to current therapies.

A novel strategy for identifying new regulatory pathways and anticancer drugs

Our approach is a novel way to do molecular biology in which unbiased high throughput screening is used to “ask the cell” to identify new pathways. We screen to develop a large database, and use simple follow-on assays and bioinformatics to identify small molecule biomodulators likely to exhibit a previously undescribed mode of action. Confirming the potential of this new strategy, our lead estrogen receptor anticancer drug candidate both induces rapid tumor regression and works by hyperactivating a normal, and previously undescribed, pathway of estrogen action in cancer. Graduate students presented 2 talks on this work at the biennial June 2014 International Congress of Endocrinology (Andruska N, Yang Mao C, Cherian M, Mahapatra L, Helferich WJ and Shapiro DJ. 2014. A Small Molecule Inhibitor Reveals a Novel Pathway of Estrogen Receptor α Action and Induces Regression of Breast Cancers, and Zheng X, Andruska, N and Shapiro DJ. 2014. A Small Molecule Inhibitor Blocks Proliferation of Ovarian Cancer Cells and Restores Sensitivity to Taxanes.)

Four papers describe this ongoing work. One paper is in press in Oncogene, one is in revision at PNAS and 2 are being written.

We also developed what is likely the first small molecule inhibitor of an oncogenic mRNA binding protein. Our inhibitor of the oncogenic mRNA binding protein IMP-1/IGF2BP1 targets oncogene mRNAs and inhibits proliferation of diverse cancer cells.

For background and more details see our Web site at www.life.uiuc.edu/shapiro . This site is accessible through the Lab Page link and in the Department of Biochemistry Web site.

Representative Publications

Andruska N, Zheng X Yang X, Helferich WG and Shapiro DJ (2014) Oncogene, In press.

Jiang X, Shapiro DJ. (2014) The immune system and inflammation in breast cancer. Mol Cell Endocrinol, 382(1): 673-82. (Recommended by Faculty of 1000 Prime)

Mahapatra L, Mao C, Andruska N, Zhang C, Shapiro DJ. (2014) High-throughput fluorescence anisotropy screen for inhibitors of the oncogenic mRNA binding protein, IMP-1. J Biomol Screen, 19(3): 427-36. PMCID: PMC2584580.

Zhang C, Nordeen SK, Shapiro DJ. (2013) Fluorescence anisotropy microplate assay to investigate the interaction of full-length steroid receptor coactivator-1a with steroid receptors. Methods Mol Biol, 977:339-51. PMCID: PMC3708604.

Cherian MT, Wilson EM and Shapiro DJ (2012) A competitive inhibitor that reduces recruitment of androgen receptor to androgen responsive genes. J. Biol. Chem. 287: 23368-23380

Andruska N, Mao C, Cherian M, Zhang C and Shapiro DJ (2012) Evaluation of a luciferase-based reporter assay as a screen for inhibitors of estrogen-ERalpha-induced proliferation of breast cancer cells. J. Biomolecular Screening, 17(7): 921-932 PMID 22498909.

Aninye IO, Berg KC, Mollo AR, Nordeen SK, Wilson, EM, and Shapiro DJ (2012) 8-Alkylthio-6-thio-substitited theophyllene analogues as selective noncompetitive progesterone receptor antagonists, Steroids, 77: 596-601. PMID 22421057.

Huang, B, Qu, Z, Ong CW, Tsang N, Xiao G., Shapiro DJ, Salto-Tellez M, Ito K, Chen L-F (2012) RUNX3 acts as a tumor supressor in breast cancer by targeting estrogen receptor alpha. Oncogene, 37:527-534. PMID 21706501.

Shapiro, DJ, Mao C and Cherian MT (2011) Small molecule inhibitors as probes for estrogen and androgen receptor action. J. Biol. Chem. 286:4043-4048 PMCID: 3039394

Woo H-H, Yi X, Lamb T, Menzl L, Baker T, Shapiro DJ, Chambers SK (2011) Posttransriptional suppression of protoconcogene c-fms by vigilin in breast cancer. Mol. Cell Biol. 31: 215-225. PMCID: 3019847

Kretzer NM, Cherian M, Mao. C, Aninye I, Reynolds P, Schiff R, Hergenrother PJ, Nordeen SK, Wilson EM and Shapiro DJ (2010) A non-competitive small molecule inhibitor of estrogen-regulated gene expression and breast cancer cell growth that enhances proteasome-dependent degradation of estrogen receptor alpha. J. Biol. Chem. 285:41863-41873. PMCID: 3017855

Powell E, Wang Y, Shapiro DJ and Xu W (2010) Differential requirements of Hsp90 and DNA for the formation of estrogen receptor homodimers. J. Biol. Chem. 285:16125-16134. PMCID: 2871481

Mao C, Pattterson NM, Cherian, MT, Aninye IO, Zhang C, Montoya JB, Cheng J, Putt KS, Hergenrother PJ, Wilson EM, Nardulli AM, Nordeen SK and Shapiro DJ 2008 A new small molecule inhibitor of estrogen receptor Α binding to estrogen response elements blocks estrogen-dependent growth of cancer cells. J Biol Chem., 283: 12819- 12830. Online: jbc.org/cgi/content/full/279/6/5025

Jiang X, Ellison SJ, Alarid, ET and Shapiro DJ 2007 Interplay between the levels of estrogen and estrogen receptor controls the level of the granzyme inhibitor, proteinase inhibitor 9 and susceptibility to immune surveillance by natural killer cells. Oncogene, 26: 4106-4114 Online: nature.com/onc/journal/v26/n28/full/1210197a

Cunningham TD, Jiang X and Shapiro, DJ 2007 Expression of high levels of human proteinase inhibitor 9 blocks both perforin/granzyme and Fas/Fas ligand-mediated cytotoxicity. Cellular Immunology, 245:32-41.

Wang S, Zhang C, Nordeen SK, and Shapiro DJ 2007 In vitro fluorescence anisotropy analysis of the interaction of full-length SRC1a with estrogen receptors alpha and beta supports an active displacement model for coregulator utilization. J. Biol. Chem., 282:2765-2775. Online: jbc.org/cgi/content/full/282/5/2765

Cheng J, Zhang C, and Shapiro DJ 2008 A functional serine 118 phosphorylation site in estrogen receptor-Α is required for down-regulation of gene expression by 17β-estradiol and by 4-hydroxytamoxifen. Endocrinology, 148: 4634-4641.

Cheng J, Yu DV, Zhou J-H and Shapiro DJ 2007 Tamoxifen induction of C/EBPΑ is required for tamoxifen-induced apoptosis. J. Biol. Chem. 282: 30535-30543