The National Institute of Diabetes & Digestive & Kidney Diseases

The primary interest of my group is mammalian development and tumorigenesis using animal model systems. We have the following three projects.

Functions of fibroblast growth factor receptors (FGFRs)

FGFRs constitute a family of four membrane-spanning tyrosine kinases, which serve as high affinity receptors for at least 22 growth factors. It has been shown that mutations in FGF receptors are responsible for at least nine human inherited diseases, all of which are caused by single amino acid mutations and exhibit extensive craniofacial, axial, and/or appendicular bone abnormalities. To study functions of FGFs/FGFRs signals in development and to gain insights into mechanisms underlying these inherited diseases, mice that carry a variety of mutations including complete, isoform, and conditional knockouts, and point mutations that mimic the human diseases have been created through gene targeting. Functional analysis of these mutant mice has been carried out.

Functions of Smad genes

Smads constitute a gene family of eight members that serve as intracellular mediators of TGF-beta signals. We have generated mouse mutants carrying targeted mutations in SMAD2-5. Our preliminary analysis on the mutant mice has revealed distinct functions of these genes in multiple biological processes.

Functions of Brca1 gene

We are studying functions of the breast tumor suppressor gene Brca1 in mammary gland development and tumor formation. Breast cancer is the most common cancer and the second leading cause of cancer mortality in women, with approximately one in nine being affected over their lifetime. Analyzing our Brca1-null, isoform, or conditional knockout models, we showed that BRCA1 is essential for genetic stability. Loss of BRCA1 increases mutation rates of all genes, including tumor suppressors and oncogenes, which results in tumor formation. We are continuing to study mechanisms of BRCA1 associated tumorigenesis and seeking efficient ways to prevent the transformation process from happening in Brca1 mutant cells.

Hyun-Seok Kim, Athanassios Vassilopoulos, Rui-Hong Wang, Tyler Lahusen, Zhen Xiao, Xiaoling Xu, Cuiling Li, Timothy D. Veenstra, Bing Li, Hongtao Yu, Junfang Ji, Xin Wei Wang, Seong-Hoon Park, Yong I. Cha, David Gius, and Chu-Xia Deng. (2011). SIRT2 Maintains Genome Integrity and Suppresses Tumorigenesis through Regulating APC/C Activity. Cancer Cell, in press

Rui-Hong Wang, Hyun-Seok Kim, Cuiying Xiao, Xiaoling Xu, Oksana Gavrilova, and Chu-Xia Deng. (2011). Hepatic SIRT1 Deficiency Results in Hyperglycemia, Oxidative Damage, and Insulin Resistance Mediated by mTORC2/AKT Signaling. JCI, in press

Suhwan Chang, Rui-Hong Wang, Keiko Akagi, Kyung-Ae Kim, Betty K. Martin, Luca Cavallone, kConFab, Diana C. Haines, Mark Basik, Phuong Mai, Elizabeth Poggi, Claudine Isaacs, Lai M. Looi, Kein S. Mun, Mark H. Greene, Stephen W. Byers, Soo H. Teo, Chu-Xia Deng and Shyam K. Sharan (2011). Tumor Suppressor BRCA1 epigenetically controls oncogenic miRNA-155. Nature Medicine, in press.

Mi-Hye Lee, Tyler Lahusen, Rui-Hong Wang, Cuiying Xiao, Xiaoling Xu, Yoo-Seok Hwang, Wei-Wu He, Yang Shi, and Chu-Xia Deng. (2011). Yin Yang 1 positively regulates BRCA1 and inhibits mammary cancer formation. Oncogene, Jun 13

Choksi S, Lin Y, Pobezinskaya Y, Chen L, Park C, Morgan M, Li T, Jitkaew S, Cao X, Kim YS, Kim HS, Levitt P, Shih G, Birre M, Chu-Xia Deng, and Liu ZG. (2011). A HIF-1 Target, ATIA, Protects Cells from Apoptosis by Modulating the Mitochondrial Thioredoxin, TRX2. Mol Cell. 42(5):597-609.

Xiaoling Xu, Beeta Ehdaie, Nobuya Ohara, Tadashi Yoshino, and Chu-Xia Deng (2010). Synergistic action of Smad4 and Pten in suppressing pancreatic ductal adenocarcinoma formation in mice. Oncogene, 4;29(5):674-86.

Athanassios Vassilopoulos, Chu-Xia Deng* (Corresponding author), Triantafyllos Chavakis* (Corresponding author). (2010). Crosstalk between the DNA damage response, histone modifications and neovascularisation. The International Journal of Biochemistry & Cell Biology, 42(2):193-7.

Hyun-Seok Kim#, Krish Patel# (#equal contribution), Kristi Muldoon-Jacobs, Kheem S. Bisht, Nukhet Aykin-Burns, J. Daniel Pennington, Riet van der Meer, Phuongmai Nguyen, Jason Savage, Kjerstin M. Owens, Athanassios Vassilopoulos, Ozkan Ozden, Keshav K. Singh, Sarki A. Abdulkadir, Douglas R. Spitz, Chu-Xia Deng* (Corresponding authors), and David Gius* (Corresponding authors). (2010). SIRT3 is a Mitochondrially Localized Tumor Suppressor Required for Maintenance of Mitochondrial Integrity and Metabolism during Stress. Cancer Cell, 17, 41-52.

T Maruyama, A Mirando, Chuxia Deng and Wei Hsu. (2010). The balance of WNT and FGF signaling influences mesenchymal stem cell fate during skeletal development. Science Signaling, 3(123):ra40.

Samuel Bunting, Nancy Wong, Hua-Tang Chen, Federica Polato, Oscar Fernandez-Capetillo, Jeremy M. Stark, Liu Cao, Xiaoling Xu, Chu-Xia Deng, Toren Finkel, Elsa Callén1, André Nussenzweig (2010). Loss of 53BP1 rescues homologous recombination in Brca1-deficient cells. Cell, 141(2):243-54.

Thomas Fishler, Yu-Ying Li, Rui-Hong Wang, Hyun-Seok Kim, Kundan Sengupta, Athanassios Vassilopoulos, Tyler Lahusen, Xiaoling Xu, Mi-Hye Lee, Qinghua Liu, Steve Elledge, Thomas Ried, and Chu-Xia Deng (2010). Genetic instability and mammary tumor formation in mice carrying mammary specific disruption of Chk1 and p53. Oncogene, 29(28):4007-17.

Chu-Xia Deng, Liu H. (2010). An unknown piece of early work of nuclear reprogramming in fish eggs. Int J Biol Sci. 6(2):190-1.

Su N, Xu X, Li C, He Q, Zhao L, Li C, Chen S, Luo F, Yi L, Du X, Huang H, Chu-Xia Deng* (Corresponding author), Chen L* (Corresponding author). (2010). Generation of Fgfr3 conditional knockout mice, Int J Biol Sci. 6(4):327-32.

Joseph A. Baur, Danica Chen, Eduardo N. Chini, Katrin Chua, Rafael deCabo, Chu-Xia Deng, Leonard, P. Guarente, David Gius, Stephen L. Helfand, Shin-Ichiro Imai, Hiroshi Itoh, Daisuke Koya, Philipp Oberdoerffer, Blanka Rogina, Manuel Serrano, David A. Sinclair, Marc Tatar, and Eric Verdin. (2010). Dietary Restriction: Standing Up for Sirtuins. Science. 329(5995):1012-3.

Hyun-Seok Kim, Cuiying Xiao, Rui-Hong Wang, Tyler Lahusen, Xiaoling Xu, Athanassios Vassilopoulos, Guelaguetza Vazquez-Ortiz, Won-Il Jeong, Ogyi Park, Sung Hwan Ki, Bin Gao, and Chu-Xia Deng. (2010). Hepatic specific disruption of SIRT6 in mice results in fatty liver formation due to enhanced glycolysis and triglyceride synthesis. Cell Metabolism, 12(3):224-36.

Vivek Shukla, Xavier Coumoul, Tyler Lahusen, Rui-Hong Wang, Xiaoling Xu, Athanassios Vassilopoulos, Cuiying Xiao, Mi-Hye Lee, Yan-Gao Man, Mutsuko Ouchi, Toru Ouchi, and Chu-Xia Deng (2010). BRCA1 Affects Global DNA Methylation through Regulation of DNMT1. Cell Research. 20(11):1201-15.

Xiao C, Kim HS, Lahusen T, Wang RH, Xu X, Gavrilova O, Jou W, Gius D, Chu-Xia Deng. (2010). SIRT6 deficiency results in severe hypoglycemia by enhancing both basal and insulin-stimulated glucose uptake in mice. J Biol Chem. 285, 36776-84.

Cuiling Li, Yi-Ping Li, Xin-Yuan Fu, and Chu-Xia Deng (2010). Anterior Visceral Endoderm SMAD4 Signaling Specifies Anterior Embryonic Patterning and Head Induction in Mice. Int J Biol Sci. 6(6):569-83.

Rui-Hong Wang, Cuiling Li, and Chu-Xia Deng (2010). Liver Steatosis and Increased ChREBP Expression in Mice Carrying a Liver Specific SIRT1 Null Mutation under a Normal Feeding Condition. Int J Biol Sci. 6(7):682-90.

Chuxia Deng (2009). SIRT1, Is It a Tumor Promoter or Tumor Suppressor? Int. J. Biol. Sci. 5: 147-152.

Matina Economopoulou, Harald F. Langer, Arkady Celeste, Valeria V. Orlova, Eun Young Choi, Mingchao Ma, Athanassios Vassilopoulos, Elsa Callen, Chuxia Deng, Craig H. Bassing, Giovanna Tosato, Manfred Boehm,

Andre Nussenzweig, and Triantafyllos Chavakis (2009). Histone H2AX is integral to hypoxia-driven neovascularisation. Nature Medicine, 15(5):553-8.

Jie Liu*, Liu Cao* (*Equal contribution), Jichun Chen, Shiwei Song, In Hye Lee, Bong-Hyun Ahn, Neil G. Kumar, Long-Yue Cao, Hongjun Liu, Ilsa I. Rovira, Keyvan Keyvanfar, Xiao-Ling Xu, Maarten van Lohuizen, Noboru Motoyama, Chu-Xia Deng and Toren Finkel (2009). Deletion of Bmi1 activates a redox-sensitive DNA damage response pathway. Nature, 459(7245):387-92.

Toren Finkel, Chu-Xia Deng *(*Corresponding author), Raul Mostoslavsky (2009). Recent progress in the biology and physiology of sirtuins. Nature, 460(7255):587-91.

Liu Cao, Xioaling Xu, Samuel F. Bunting, Rui-Hong Wang, Jie Liu, Longyue L. Cao, Junjie Chen, Andre Nussenzweig, Chu-Xia Deng* (*Corresponding author) and Toren Finkel* (*Corresponding author) (2009). A selective requirement for 53BP1 in the biological response to genomic instability induced by Brca1 deficiency. Molecular Cell, 35(4):534-41.

Sang Soo Kim, Liu Cao, Hye Jung Baek, Sung-Chul Lim, Cuiling Li, Rui-Hong Wang, Xiaoling Xu, Kwan Ho Cho, and Chu-Xia Deng. (2009). Impaired skin and mammary gland development and increased g-irradiation-induced tumorigenesis in mice carrying a targeted mutation of the S1152-ATM phosphorylation site in Brca1. Cancer Research, 69(24):9291-300.

Jian-Sheng Kang, Jin-Hua Tian1, Ping-Yue Pan, Philip Zald, Cuiling Li, Chuxia Deng, and Zu-Hang Sheng. (2008). Docking of Axonal Mitochondria by Syntaphilin Controls their Mobility and Affects Short-term Facilitation. Cell 132(1):137-48.

Yin L, Du X, Li C, Xu X, Chen Z, Su N, Zhao L, Qi H, Li F, Xue J, Yang J, Jin M, Chu-Xia Deng*, Chen L* (*Corresponding authors). (2008). A Pro253Arg mutation in fibroblast growth factor receptor 2 (Fgfr2) causes skeleton malformation mimicking human Apert syndrome by affecting both chondrogenesis and osteogenesis. Bone 42: 631-643.

Athanasios Vasilopoulos, Rui-Hong Wang, Constantinos Petrovas, David Ambrozac, Richard Koup and Chu-Xia Deng (2008). Identification and characterization of cancer initiating cells from BRCA1-associated mammary tumors using markers for normal mammary stem cells. Int. J. Biol. Sci. 4: 133-142.

Ahn BH*, Kim HS*(*Equal contribution), Song SW, Lee IH, Liu J, Chuxia Deng* (*Corresponding authors), and Finkel T. (2008). The mitochondrial deacetylase SIRT3 regulates energy homeostasis. PNAS 105(38):14447-52.

Wang RH, Sengupta K, Li C, Kim HS, Cao L, Xiao C, Kim SS, Xu X, Zheng Y, Chilton B, Jia R, Zheng ZM, Appella E, Wang XW, Ried T, and Chuxia Deng (2008). Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer Cell 14, 312–323.

Wang RH, Zheng Y, Kim HS, Xu X, Cao L, Luhasen T, Lee MY, Xiao C, Vassilopoulos A, Chen W, Man YG, Hung MC, Finkel T, and Chuxia Deng (2008). Interplay among BRCA1, SIRT1, and SURVIVIN during BRCA1-associated Tumorigenesis. Mol. Cell 32, 11–20.

Vivek Shukla, Xavier Coumoul, Athanassios Vassilopoulos, Chuxia Deng (2008). IGF signaling pathway as a selective target of familial breast cancer therapy. Current Molecular Medicine 8(8):727-40.

Yohei Tominaga, Anran Wang, Xiaoyan Wang, Rui-Hong Wang, Liu Cao and Chuxia Deng (2007). Genistein inhibits Brca1 mutant tumor growth through activation of DNA damage checkpoints, cell cycle arrest and mitotic catastrophe. Cell Death and Differentiation 14(3):472-9.

Niwa Y, Masamizu Y, Liu T, Nakayama R, Deng CX, Kageyama R. (2007). The initiation and propagation of hes7 oscillation are cooperatively regulated by fgf and notch signaling in the somite segmentation clock. Dev Cell 13(2):298-304.

Li W, Xiao C, Vonderhaar BK, Deng CX. (2007). A role of estrogen/ERalpha signaling in BRCA1-associated tissue-specific tumor formation. Oncogene 26(51):7204-12.

Shukla V, Coumoul X, Deng CX (2007). RNAi-based conditional gene knockdown in mice using a U6 promoter driven vector. Int J Biol Sci. (3): 91-9.

Cao L, Xu X, Cao LL, Wang RH, Coumoul X, Kim SS, Deng CX. (2007). Absence of full-length Brca1 sensitizes mice to oxidative stress and carcinogen-induced tumorigenesis in the esophagus and forestomach. Carcinogenesis 28(7):1401-7.

Izeradjene K, Combs C, Best M, Gopinathan A, Wagner A, Grady WM, Deng CX, Hruban RH, Adsay NV, Tuveson DA, Hingorani SR. (2007). Kras(G12D) and Smad4/Dpc4 haploinsufficiency cooperate to induce mucinous cystic neoplasms and invasive adenocarcinoma of the pancreas. Cancer Cell 11(3):229-43.

Wang X, Liu L, Montagna C, Ried T, Deng CX. (2007). Haploinsufficiency of Parp1 accelerates Brca1-associated centrosome amplification, telomere shortening, genetic instability, apoptosis, and embryonic lethality. Cell Death Differ. 14(5):924-31.

Li W, Sandhoff R, Kono M, Zerfas P, Hoffmann V, Ding BC, Proia RL, Deng CX. (2007). Depletion of ceramides with very long chain fatty acids causes defective skin permeability barrier function, and neonatal lethality in ELOVL4 deficient mice. Int J Biol Sci. 3(2):120-8.

Zhao M, Li D, Shimazu K, Zhou YX, Lu B, Deng CX. (2007). Fibroblast Growth Factor Receptor-1 Is Required for Long-Term Potentiation, Memory Consolidation, and Neurogenesis. Biol Psychiatry 62(5):381-90.

Xiao C#, Sharp JA# (#equal contribution), Kawahara M, Davalos AR, Difilippantonio MJ, Hu Y, Li W, Cao L, Buetow K, Ried T, Chadwick BP, Deng CX* (*Corresponding authors), Panning B*(*Corresponding authors). (2007). The XIST noncoding RNA functions independently of BRCA1 in X inactivation. Cell 128(5):977-89.

Shukla V, Coumoul X, Wang RH, Kim HS, Deng CX. (2007). RNA interference and inhibition of MEK-ERK signaling prevent abnormal skeletal phenotypes in a mouse model of craniosynostosis. Nat Genet. 39(9):1145-50. Commentes by Andrew O M Wilkie, Nature Genetics 39 (9), 1057-1059, and Chuxia Deng (2007). Editorial: In Celebration of Dr. Mario R. Capecchi's Nobel Prize. Int. J. Biol. Sci. 3: 417-419.