Ph.D. - Massachusetts Institute of Technology
Post Doctoral - Harvard University
174 Rightmire Hall
1060 Carmack Road
Columbus, OH 43210
- Molecular mechanisms of diseases
- Breast cancer
- Stress responses
- Signal transduction and gene expression
- Stromal cancer interactions and metastasis
- Islet cell biology and transplantation
- Inflammation in disease context
Introduction: Maladaptation of cells to various signals plays important roles in the pathogenesis of many human diseases. The current focus of my laboratory is to study the maladaptive processes in the development of breast cancer and diabetes. In both diseases, inflammatory signals exacerbate the diseases. We are investigating how inflammatory signals in conjunction with other stress signals affect various cellular machineries that regulate signal transduction, transcription, apoptosis, cell migration, angiogenesis, and metastasis.
The approach we take is to focus on a stress-inducible gene ATF3, which encodes a member of the ATF/CREB transcription factors. Our strategy is to use ATF3 — as a handle — to probe the stress responses and gain insights to the roles of cellular adaptations to stress signals in disease development.
ATF3 as an adaptive-response gene and a “hub” in the biological networks: ATF3 is a member of the ATF/CREB transcription factors, which all share a common DNA binding motif — the basic region-leucine zipper (bZip) motif — and bind to the consensus sequence TGACGTCA in vitro, albeit with different affinity. Overwhelming evidence indicates that ATF3 is induced by a variety of stress signals. However, some of the signals that induce ATF3 expression do not fit the conventional definition of stress signals. Thus, it is overly simplistic to characterize ATF3 as a stress-inducible gene; rather, we suggest characterizing it as an adaptive-response gene that participates in cellular processes to adapt to extra- and/or intra-cellular changes. The list of the signals that can induce ATF3 expression is considerably long, including some seemingly unrelated or sometimes conflicting signals such as cytokines, calcium influx, hypoxia, nutrient deprivation, and serum stimulation. Thus, it appears that ATF3 is a key gene for the cells to respond to perturbation of cellular homeostasis. Borrowing the hub concept from the network theory, we suggest that ATF3 is a “hub” in the biological networks (Fig. 1).
Breast cancer research: We found that ATF3 has a dichotomous role in cancer development. It functions as a tumor suppressor in non-transformed mammary epithelial cells but an oncogene in malignant breast cancer cells. Thus, how the cells “interpret” the expression of ATF3, an adaptive-response gene, depends on the “context” of the cells — the milieu of various events ongoing in the cells. In the malignant breast cancer cells, ATF3 promotes cell motility and up-regulates many genes involved in epithelia-mesenchymal transition (EMT), further supporting an oncogenic role of ATF3 in this context. Interestingly, the ATF3 gene is amplified and its expression up-regulated in most of the breast tumor samples we have examined thus far (>200 samples for expression studies), suggesting that ATF3 is likely to play a relevant role in human breast cancer development. We are now examining the roles of ATF3 in stroma-cancer interactions and tumor metastasis. In light of the recent findings that ATF3 regulates innate immune response — a process known to play an important role in cancer development — we are also examining the roles of ATF3 in the interplays between innate immunity and cancer development (Fig. 2).
Diabetes research: We found that ATF3 is induced in the pancreatic beta cells by many stress signals relevant to diabetes, including inflammatory cytokines, high fatty acids, and high glucose. Functionally, induction of ATF3 promotes apoptosis in the beta cells (Fig. 2) and our data indicate that it does so, at least in part, by repressing IRS2, a potent pro-survival factor in beta cells. Deletion of ATF3 protects beta cells from stress-induced apoptosis under various paradigms. Based on these findings, we are testing the idea that deletion of ATF3 “dampens” islet stress responses and may protect beta cells in islets transplantation. In addition to the roles of ATF3 in the islets — the graft — we are also testing the roles of ATF3 in the host immune system to determine how it may affect the host-graft interactions. Since islet transplantation is a clinically viable treatment for diabetes, these studies may lead to future applications to improve therapy for diabetes.
Techniques and Models: The methods we use include those in the areas of biochemistry, molecular biology, genetics, cell biology, pathology, and physiology. The experimental systems we use include mammalian cells (primary and cell lines), transgenic/knockout mice, and clinical samples.
- Molecular biology: Cloning, BAC recombineering, RNA preparation and analyses (real-time PCR, northern), RNAi, immuno-blotting, EMSA, chromatin immunoprecipitation (ChIP), kinase assays, and transcription assays.
- Cell biology: in situ hybridization, immnuocytochemistry, apoptosis assays, cell cycle analyses, immunofluorescent assay, confocal microscopy, cell motility assay, angiogenesis assay, and analyses of macrophages.
- Biochemistry: protein production by various expression systems, protein fractionation and chromatography.
- Genetics and physiology: xenograft tumor models, syngeneic and allogeneic islet transplantation in mice, production and analyses of genetically modified mice, including transgenic, knock-out, and knock-in mice.
- Microarray, proteomics, and bioinformatics
- Tanabe K, Liu Y, Hansan, SD, Martinez SC, Cras-Mèneur C, Welling CM, Bernal-Mizrachi E, Tanizawa Y, Rhodes CJ, Zmuda EJ, Hai T, Abumrad NA, and Permutt MA, Glucose and fatty acids synergize to promote ß-cell apoptosis through activation of glycogen synthase kinase 3ß independent of JNK activation, PLoS One 6(4): e18146, doi:10.1371/journal.pone.0018146 (2011). PMCID: PMC308252
- Hasin T, Elhanani O, Kehat I, Hai T, and Aronheim A, Angiotensin II signaling up-regulates the immediate early transcription factor ATF3 in the left but not the right atrim. Basic Res. Cardiol. 106:175-187, (2011). PMID: 21191795
- St. Germain C, Niknejad N, Ma L, Garbuio K, Hai T, Dimitroulakos J., Cisplatin induces cytotoxicity through the mitogen-activated protein kinase pathways and AATF3. Neoplasia 12:527-538 (2010). PMCID: PMC2907579
- Majumder S, Roy S, Kaffenberger T, Wang B, Costinean S, Frankel W, Bratasz A, Kuppusamy P, Hai T, Ghoshal K and Jacob ST. 2010. Loss of metallothionein predisposes mice to diethylnitrosamine-induced hepatocarcinogenesis by activating NFKB target genes. Cancer Res. 70:10265-10276 (2010). PMCID: PMC3059562
- Yin X, Wolford CC, Chang YS, McConoughy S, Ramsey S, Aderem A, and Hai T, The roles of ATF3, an adaptive-response gene, in TGF signaling and breast cancer stem cell features. J. Cell Sci. 123:3558-3565 (2010). PMCID: PMC2951469
- Zmuda EJ, Qi L, Zhu MX, Mirmira RG, Montminy MR, and Hai T, The roles of ATF3, an adaptive-response gene, in high fat diet induced diabetes and pancreatic B-cell dysfunction. Mol. Endo. 24:1423-1433 (2010). PMCID: PMC2903910
- Akarm A, Han B, Masoom H, Peng C, Lam E, Litvak M, Bai X, Shan Y, Hai T, Batt J, Slutsky AS, Zhang H, Kuebler WM, Haitsma JJ, Liu M, dos Santos CC, Activating transcription factor 3 confers protection against ventilator induced lung injury. AM. J. Resp. Crit. Care Med., 182:489-500 (2010). PMCID: PMC2937241
- Takii R, Inouye S, Fujimoto M, Nakamura T, Shinkawa T, Prakasam R, Tan K, Hayashida N, Ichikawa H, Hai T, Nakai A, Heat shock transcription factor 1 inhibits induction of IL-6 through inducing activation transcription factor 3. J. Immunol. 184:1041-1048 (2010). PMID: 20018623
- Zmuda EJ, Viapiano M, Grey ST, Hadley G, Garcia-Ocaña A, and Hai T, Deficiency of ATF3, an adaptive-response gene, protects islets and ameliorates inflammation in a syngeneic transplantation model. Diabetologia. 53:1438-1450 (2010) PMCID: PMC2877761
- Liang Y, Jiang H, Ratovitskia T, Jie C, Nakamura M, Hirschhornd RR, Wang X, Smith WW, Hai T, Poirier MA, Ross, CA, ATF3 plays a protective role against toxicity by N-terminal fragment of mutant huntingtin in stable PC12 cell, Brain Res. 1286:221-229 (2009).
- Qi L, Saberi M, Zmuda ER, Wang Y, Altarejos J, Zhang X, Dentin R, Hedrick S, Bandyopadhyay G, Hai T, Olefsky J, Montminy M, Adipocyte CREB Promotes Insulin Resistance in Obesity, Cell Metabolism. 9(3):277-86 (2009).
- Wang Q, Mora-Jensen H, Weniger MA, Perez-Galan P, Wolford CC, Hai T, Ron D, Chen W, Trenkle W, Wiestner A, Ye Y, ERAD inhibitors integrate ER stress with an epigenetic mechanism to activate BH3 only protein NOXA in cancer cells, Proc. Natil. Acad. Sci. USA. 106(7):2200-5 (2009).
- Sawamura N, Ando T, Maruyama Y, Fujimuro M, Mochizuki H, Honjo K, Shimoda M, Toda H, Sawanura-Yamamoto T, Makuch LA, Hayashi A, Ishizuka K, Cascella NG, Kamiya A, Ishida N, Tomoda T, Hai T, Furukubo-Tokunaga K, and Sawa A, Nuclear DISC1 modulates ATF4/CREB2-mediated gene transcription. Molecular Psychiatry. 13:1138-1148 (2008).
- Cunha DA, Hekerman P, Ladrière L, Bazarra-Castro A, Ortis F, Wakeham MC, Moore F, Rasschaert J, Cardozo AK, Bellomo E, Overbergh L, Mathieu C, Lupi R, Hai T, Herchuelz A, Marchetti P, Rutter G, Eizirik DL, Cnop M, Initiation and execution of lipotoxic ER stress in pancreatic ß cells. J. Cell Sci. 121:2308-2318 (2008).
- Li D, Yin X, Wolford CC, Zmuda ER, Dong X, White M, and Hai T, The repression of IRS2 gene by ATF3, a stress-inducible gene, contributes to pancreatic ß-cell apoptosis. Diabetes 57:635-644, 2008.
- Yin X, DeWille J, and Hai T, A potential dichotomous role of ATF3, an adaptive-response gene, in cancer progression. Oncogene 27:2118-2127, 2008.
- Inouye S, Fujimoto M, Nakamura T, Takaki E, Hayashida N, Hai T, and Nakai A, HSF1 opens chromatin structure of IL-6 promoter to facilitate binding of an activator or a repressor. J. Biol. Chem. 282:33210-33217, 2007.
- Whitmore MM, Iparraguirre A, Kubelka L, Weninger W, Hai T, and Williams BRG, Negative Regulation of Toll-Like Receptor Signaling Pathways by Activating Transcription Factor-3. J. Immunol. 179:3622-3630, 2007.
- Ameri K, Culmsee C, Penninger J, Katschinski DM, Wenger R, Hai T, Wagner E, and Harris AL, Anoxic induction of Activating transcription factor 3 (ATF3) mediated independent of HIF-1 by Jun Kinase pathways. Oncogene 26:284-289, 2007.
- Khuu C, Barrozo R, Hai T, and Weinstein SL, Activating transcription factor 3 (ATF3) represses the transcription of CCL4 in murine macrophages. Mol. Immunol. 44:1598-1605, 2007.
- Bandyopadhyay S, Wang Y, Zhan R, Pai SK, Watabe M, Iiizumi M, Furuta E, Mohinta S, Liu W, Hirota S, Hosobe S, Tsukada T, Miura K, Takano Y, Saito K, Commes T, Piquemal D, Hai T, and Watabe K, The tumor metastasis suppressor gene Drg-1 down regulates the expression of ATF3 in prostate cancer. Cancer Res. 66:11983-11990, 2006.
- Lu D, Chen J, and Hai T, The regulation of ATF3 gene expression by mitogen-activated protein kinases. Biochem. J. 401:559-567, 2007.
- Hai T. The ATF transcription factors in cellular adaptive responses. In J. Ma (ed.), Gene expression and regulation. Pages 329-340, Higher Education Press, Beijing, China, and Springer, New York, USA. 2006. (Book chapter)
- Hai T, Lu D, Wolford CC. Transcription factors: ATF. In G. J. Laurent and S. D. Shaprio (ed.), Encyclopedia of respiratory medicine. Pages 257-259, Elsevier, Oxford, UK. 2006. (Book chapter)
- Gilchrist M, Thorsson V, Li B, Rust AG, Korb M, Kennedy K, Hai T, Bolouri H, and
- Lu D, Wolfgang, CD, and Hai T. ATF3, a stress-inducible gene, suppresses Ras-stimulated tumorigenesis. J. Biol. Chem. 281:10473-10481, 2006.
- Yuo JS., McEachin RC, Cui TX, Duggal NK, Hai T, States DJ, and Schwartz J. Profiles of growth hormone regulated genes reveal time-dependent responses and identify a mechanism for regulation of activating transcription factor 3 by growth hormone. J. Biol. Chem. 281:4132-4141, 2006.
- Yan C, Lu D, Hai T, Boyd DD. ATF3 is a regulator of p53 stability in the genotoxic response. EMBO J. 24:2425-2435, 2005.
- Hartman MG, Lu D, Kim M-L, Kociba GJ, Shukri T, Buteau J, Wang X, Frankel WL, Guttridge D, Prentki M, Grey ST, Ron D, Hai T. A role for ATF3 in stress-induced ß cell apoptosis. Mol. Cell. Biol. 24:5721-5732, 2004.
- Jiang H-Y, Wek SA, McGrath CC, Lu D, Hai T, Harding HP, Wang X, Ron DC, Wek RC. ATF3 is integral to the eIF2 kinase stress response. Mol. Cell. Biol. 24:1365-1377, 2004.
- Ameri K, Lewis CE, Raida M, Sowter H, Hai T, Harris AL. Anoxic induction of ATF-4 via HIF-1 independent pathways of protein stabilization in human cancer cells. Blood 103:1876-1882, 2004.
- Hashimoto Y, Zhang C, Kawauchi J, Imoto I, Adachi MT, Inazawa J, Amagasa T, Hai T, Kitajima S. Isolation of a novel form of the alternatively spliced transcriptional repressor ATF3 and its activation in response to stress stimuli. Nucl. Acid. Res. 30:2398-2306, 2002.
- Allen-Jennings AE, Hartman MG, Kociba GJ, Hai T. The roles of ATF3 in liver dysfunction and the regulation of PEPCK gene expression. J. Biol. Chem. 277:20020-20025, 2002.
- Allen-Jennings AE, Hartman MG, Kociba GJ, Hai T. The roles of ATF3 in glucose homeostasis: A transgenic mouse model with liver dysfunction and defects in endocrine pancreas. J. Biol. Chem. 276:29507-29514, 2001.
- Okamoto Y, Chaves A, Chen J, Kelley R, Jones K, Weed HG, Gardner KL, Gangi L, Yamaguchi M, Klomkleaw W, Nakayama T, Hamlin RL, Carnes CA, Altschuld RA, Bauer JA, Hai T. Transgenic mice expressing ATF3 in the heart have conduction abnormalities and contractile dysfunction. Am. J. Pathol. 159:639-650, 2001.
- Hartman MG, Hai T. The molecular biology and nomenclature of the ATF/CREB family of transcription factors: ATF proteins and homeostasis. Gene 273:1-11, 2001. (Review)
- Lassot I, Ségéral E, Berlioz-Torrent C, Durand H, Groussin L, Hai T, Benarous R, Margottin-Goguet F. ATF4 degradation relies on a phosphorylation-dependent interaction with the SCFßTrCP ubiquitin ligase. Mol. Cell. Biol. 21:2192-2202, 2001.
- Wolfgang CD, Liang G, Okamoto Y, Allen AE, Hai T. Transcriptional autorepression of the stress-inducible gene ATF3. J. Biol. Chem. 275:16865-16870, 2000.
- Hai T, Wolfgang CD, Marsee DK, Allen AE, Sivaprasad U. ATF3 and stress responses, Gene Expression 7:321-335, 1999. (Review)
- Fawcett TW, Martindale JL, Guyton KZ, Hai T, Holbrook NJ. Complexes containing ATF/CREB interact with the C/EBP-ATF composite site to regulate Gadd153 expression during stress response. Biochemical J. 339:135-141, 1999.