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Zhang Laboratory

Welcome to Jennifer Zhang's lab homepage.  Our lab is in the Department of Dermatology and is located in the School of Medicine at Duke University.

Research

Epidermis of the skin constitutes the largest organ and the outer most barrier of the body. It is one of the few organs that undergo lifelong self-renewal through a tight balance of cell growth, differentiation, and programmed cell death. Deregulation of this balance is manifested in many diseases, including various immune diseases and cancer. 

Our lab is focused on 3 interrelated topics:

1. Gene regulation of epithelial cell proliferation and differentiation

Using regenerated human skin tissues and murine genetic models, we have demonstrated important functions NF-kB and AP-1 gene regulators in epidermal cell growth and differentiation. Currently, our efforts are focused on understating how loss-of-function of CYLD, a deubiquitinase and tumor suppressor, leads to the development of hair follicle defects, skin inflammation, and cancer. Specifically, we want to determine how CYLD integrates NF-kB, AP1, Myc, and other transcription factors to control epidermal cell growth and lineage differentiation.

De novo skin regeneration is life-saving procedure for severely burned patients and lethal genetic skin diseases such as epidermal bullosa. An additional aspect of our study is to improve new skin regeneration techniques and to create experimental skin disease models with gene transduced keratinocytes, as illustrated below.

2. Keratinocytes as instigators of inflammatory responses

Keratinocytes are constantly challenged by external insults, as well as immune cells. Disarray of the crosstalk between keratinocytes and immune cells underlies various immune diseases, including dermatitis, psoriasis, and cutaneous graft-versus-host disease (GVHD). GVHD is a common complication and the leading cause of non-relapse mortality among patients after receiving allogenic hematopoietic stem cell transplantation.  The skin is the most commonly affected organ in both the acute and chronic forms of this disease.  Treatment options for GVHD are limited and the current standard therapy is high dose systemic corticosteroid which is itself associated with significant morbidity. Our goal is to understand how keratinocytes contribute to the progression of GVHD, and may therefore be targeted to mitigate the disease.

3. Ubiquitination enzymes in melanoma

Melanoma most lethal and difficult to treat skin cancer. In the recent years, BRAF/MEK-targeted therapies have produced exciting results, but they suffer from short duration. Our goal is to uncover novel mechanisms crucial for melanoma malignancy. Specifically, we want to understand how ubiquitination enzymes contribute to melanoma growth. Previously, we have demonstrated that CYLD inhibits melanoma growth through suppression of JNK/AP1 and b1-integrin signaling pathways. In contrast, UBE2N, a K63-Ubiquitin conjusage, promotes melanoma growth in part through activation of the MEK/FRA/SOX10 signaling cascade. Currently, our efforts are focused on understanding how UBE2N and other ubiquitin enzymes regulate the MAPK signaling pathway and whether they can be targeted for melanoma therapy.

Research Staff

Anushka Dikshit - PhD

PostDoc

Yingai Jane Jin - PhD

Research Specialist

Simone Degan - PhD Research Specialist
Yuyang Yue - MS Visiting Researcher

 

Publications

Dikshit A, Jin YJ, Degan S, Hwang J, Foster MW, Li CY and Zhang JY. UBE2N promotes melanoma growth via MEK/FRA1/SOX10 signaling.  Cancer Res. 2018 Sep 17, PMD40223745

Wang, Y., Zhang, G., Jin, J., Degan, S., Tameze, Y., and Zhang, JY. MALT1 promotes melanoma progression through JNK/c-Jun signaling. Oncogenesis 6, e365. 2017, PMC5541718

Sachan R., Jaipan P., Zhang JY., Degan S., Erdmann D., Tedesco J., Vanderwal L., Stafslien SJ., Negut, I. Visan A., Dorcioman G., Socol G., Cristescu R., Chrisey DB., and Narayan RJ. Printing amphotericin B on microneedles using matrixassisted pulsed laser evaporation. International J. of Bioprinting. 2017 July; 3(2), 1-11. http://ijb.whioce.com/index.php/int-j-bioprinting/article/view/117

Zhang X., Luo S., Wu J., Zhang L. Wang WH., Degan S., Erdmann D., Hall R. and Zhang JY. KIND1 Loss Sensitizes Keratinocytes to UV-induced Inflammatory Response and DNA Damage. J. Invest. Dermatol. 2017 Feb;137(2):475-483.  PMCID:PMC5258776

Jin YJ, Wang S, Cho J, Selim MA, Wright T, Mosialos G, Zhang JY. Epidermal CYLD inactivation sensitizes mice to the development of sebaceous and basaloid skin tumors. JCI Insight. 2016 July; 1(11), 1-11. PMCID: PMC4966682.

Zhang X, Wu J, Luo S, Lechler T, Zhang JY. FRA1 promotes squamous cell carcinoma growth and metastasis through distinct AKT and c-Jun dependent mechanisms. Oncotarget. 2016 Apr 29; PMID: 27144339.

Chen Y, Fang Q, Wang Z, Zhang JY, MacLeod AS, Hall RP, Liedtke WB. Transient Receptor Potential Vanilloid 4 Ion Channel Functions as a Pruriceptor in Epidermal Keratinocytes to Evoke Histaminergic Itch. J Biol Chem. 2016 May 6;291(19):10252-62.  PMCID: PMC4858974.

Zhang JY, Wang Y. Jin J, Degan S. Hall RP, Boehm RD, Jaipan P and Naraya RJ. Use of Drawing Lithography-Fabricated Polyglycolic Acid Microneedles for Transdermal Delivery of Itraconazole to a Human Basal Cell Carcinoma Model Regenerated on Mice. JOM (the journal of the Minerals, Metals & Materials Society). p1-6, Feb, 2016 http://link.springer.com/article/10.1007/s11837-016-1841-1/fulltext.html

Zhang XY, Wu J, Jin YJ, Qin J, Streilein, R, Hall P and Zhang JY. RNA-Seq and ChIP-Seq reveals SQSTM1/p62 as a key mediator of JunB suppression of NF-kB-dependent proinflammation J. Invest Dermtol. 135 (4), 1016-24, 2015. PMCID: PMC4366298.

Wilson JW, Degan S, Gainey CS, Mitropoulos T, Simpson MJ, Zhang JY, Warren WS. Comparing in vivo pump-probe and multiphoton fluorescence microscopy of melanoma and pigmented lesions. J Biomed Opt. 20(5):051012. 2015. PMCID: PMC4409034.

Liedtke W, Zhang JY, Hall RP, 3rd, Steinhoff M. Keratinocyte growth regulation TRP-ed up over downregulated TRPV4? J. Invest Dermatol 134(9): 2310-2312, 2014. PMID:25120148.

Ke H, Christy Augusta, Doug Tyler, Gandham VD, Jin YJ, Hall RP and Zhang JY. JNK and b1-integrin signaling pathways underlie melanoma growth and metastasis in lieu of CYLD-deficiency. J. Invest. Derm., 133(1):221-9, 2013. PMCID: PMC3485435.

Gandham VD, Maddala RL, Rao V, Epstein DL, Hall RP, Zhang JY.  Effects of Y27632 on keratinocyte procurement and wound healing.  Clin Exp Dermatol. 2013 Oct; 38(7):782-6. PMID: 23675999

Ke H, Augustine CK, Gandham VD, Jin JY, Tyler DS, Akiyama SK, Hall RP, Zhang JY.  CYLD inhibits melanoma growth and progression through suppression of the JNK/AP-1 and ß1-integrin signaling pathways. J Invest Dermatol. 2013 Jan;133(1): 221-9. PMID: 22832488

Zhang JY, Selim MA.  The role of the c-Jun N-terminal Kinase signaling pathway in skin cancer.  Am J Cancer Res. 2012; 2(6):691-8.  PMID: 23226615

Miliana de Marval P. Lutfeali S, Jin JY, Leshin B, Selim MA, Zhang JY. CYLD inhibits tumorigenesis and metastasis by blocking JNK/AP1 signaling at multiple levels.  Cancer Prev Res (Phila).  2011 Jun;4(6):851-9. PMID: 21478324

Matthews TE, Wilson JW, Degan S, Simpson MJ, Jin JY, Zhang JY, Warren WS. In vivo and ex vivo epi-mode pump-probe imaging of melanin and microvasculature.  Biomed Opt Express. 2011 Jun 1;2(6):1576-83.  PMID: 21698020

Jin JY, Ke H, Hall RP, Zhang JY. c-Jun promotes whereas JunB inhibits epidermal neoplasia. J Invest Dermatol. 2011 May;131(5):1149-58. PMID: 21289643

Ke H, Harris R, Coloff JL, Jin JY, Leshin B, Miliani de Marval P, Tao S. Rathmell JC, Hall RP, Zhang JY.  The c-Jun NH2-terminal kinase 2 plays a dominant role in human epidermal neoplasia.  Cancer Res. 2010 Apr 15;70(8):3080-8.  PMID: 20354187

Alder AS, Sinha S, Kawahara TL, Zhang JY, Segal E. Chang HY.  Motif module map reveals enforcement of aging by continual NF-kappaB activity.  Genes Dev. 2007 Dec 15;21(24):3244-57.  PMID: 18055696

Zhang JY, Adams AE, Ridky TW, Tao S. Khavari PA.  Tumor necrosis factor receptor 1/c-Jun-NH2-kinase signaling promotes human neoplasia.  Cancer Res. 2007 Apr 15;37(8):3827-34.  PMID: 17440097

Zhang JY, Tao S, Kimmel R, Khavari PA.  CDK4 regulation by TNFR1 and JNK is required for NF-kappaB-mediated epidermal growth control.  J Cell Biol. 2005 Feb 14;168(4): 561-6. PMID: 15699216

Zhang JY, Green CL, Tao S, Khavari PA.  NF-kappaB ReIA opposes epidermal proliferation driven by TNFR1 and JNK.  Genes Dev. 2004 Jan 1;18(1):17-22.  PMID: 14724177

Hinata K, Gervin AM, Zhang JY, Khavari PA.  Divergent gene regulation and growth effects by NF-kappa B in epithelial and mesenchymal cells of human skin.  Oncogene. 2003 Apr 3;22(13):1955-64.  PMID: 12673201

Lazarov M, Green CL, Zhang JY, Jubo Y, Dajee M, Khavari PA.  Escaping G1 restraints on neoplasia--Cdk4 regulation by Ras and NF-kappa B.  Cell Cycle. 2003 Mar-Apr;2(2):79-80.  PMID: 12695650

Dajee M, Lazarov M, Zhang JY, Cai T, Green CL, Russell AJ, Marinkovich MP, Tao S, Lin Q, Kubo Y, Khavari PA.  NF-kappaB blockade and oncogenic Ras trigger invasive human epidermal neoplasia.  Nature. 2003 Feb 6;421(6923):639-43.  PMID: 12571598