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J. Alan Diehl, PhD
Professor of Biochemistry & Molecular Biology
College of Medicine
MUSC

Email: diehl@musc.edu
 
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J. Alan Diehl, PhD

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Research Interest:

The overarching goal of the research conducted within my laboratory is the discovery of molecular mechanisms that contribute to uncontrolled cell proliferation and decreased cell death, which are collectively associated with neoplastic growth. My group has focused on two key regulatory pathways to achieve this goal: cell division and signal transduction pathways that regulate cellular response to stress. My laboratory has made high impact discoveries with regard to deregulated cell division and cancer, interconnections between cell division and epigenetic regulation, and the role of the unfolded protein response in tumor progression.

Positions:
Associate Director of Basic Sciences, Hollings Cancer Center, Medical University of South Carolina

Selected Publications:

1.Maas NL, Singh N, Diehl JA. Generation and characterization of an analog-sensitive PERK allele. Cancer Biol Ther. .15(8):1106-11, 2014. PMCID: PMC4119078
View in: PubMed

2.Pytel D, Seyb K, Liu M, Ray SS, Concannon J, Huang M, Cuny GD, Diehl JA, Glicksman MA. Enzymatic Characterization of ER Stress-Dependent Kinase, PERK, and Development of a High-Throughput Assay for Identification of PERK Inhibitors. J Biomol Screen. .19(7):1024-1034, 2014.
View in: PubMed

3.Natsuizaka M, Kinugasa H, Kagawa S, Whelan KA, Naganuma S, Subramanian H, Chang S, Nakagawa KJ, Rustgi NL, Kita Y, Natsugoe S, Basu D, Gimotty PA, Klein-Szanto AJ, Diehl JA, Nakagawa H. IGFBP3 promotes esophageal cancer growth by suppressing oxidative stress in hypoxic tumor microenvironment. Am J Cancer Res. .4(1):29-41, 2014. PMCID: PMC3902230
View in: PubMed

4.Lee EK, Lian Z, D'Andrea K, Letrero R, Sheng W, Liu S, Diehl JN, Pytel D, Barbash O, Schuchter L, Amaravaradi R, Xu X, Herlyn M, Nathanson KL, Diehl JA. The FBXO4 tumor suppressor functions as a barrier to BRAFV600E-dependent metastatic melanoma. Mol Cell Biol. .33(22):4422-33, 2013. PMCID: PMC3838190
View in: PubMed

5.Basu D, Bewley AF, Sperry SM, Montone KT, Gimotty PA, Rasanen K, Facompre ND, Weinstein GS, Nakagawa H, Diehl JA, Rustgi AK, Herlyn M. EGFR inhibition promotes an aggressive invasion pattern mediated by mesenchymal-like tumor cells within squamous cell carcinomas. Mol Cancer Ther. .12(10):2176-86, 2013. PMCID: PMC3796003
View in: PubMed

6.Chitnis N, Pytel D, Diehl JA. UPR-inducible miRNAs contribute to stressful situations. Trends Biochem Sci. .38(9):447-52, 2013. PMCID: PMC4056666
View in: PubMed

7.Grugan KD, Vega ME, Wong GS, Diehl JA, Bass AJ, Wong KK, Nakagawa H, Rustgi AK. A common p53 mutation (R175H) activates c-Met receptor tyrosine kinase to enhance tumor cell invasion. Cancer Biol Ther. .14(9):853-9, 2013. PMCID: PMC3909554
View in: PubMed

8.Young RM, Ackerman D, Quinn ZL, Mancuso A, Gruber M, Liu L, Giannoukos DN, Bobrovnikova-Marjon E, Diehl JA, Keith B, Simon MC. Dysregulated mTORC1 renders cells critically dependent on desaturated lipids for survival under tumor-like stress. Genes Dev. .27(10):1115-31, 2013. PMCID: PMC3672646
View in: PubMed

9.Vaites LP, Lian Z, Lee EK, Yin B, DeMicco A, Bassing CH, Diehl JA. ATM deficiency augments constitutively nuclear cyclin D1-driven genomic instability and lymphomagenesis. Oncogene. .33(1):129-33, 2013. PMCID: PMC4112739
View in: PubMed

10.Sayers CM, Papandreou I, Guttmann DM, Maas NL, Diehl JA, Witze ES, Koong AC, Koumenis C. Identification and characterization of a potent activator of p53-independent cellular senescence via a small-molecule screen for modifiers of the integrated stress response. Mol Pharmacol. .83(3):594-604, 2012. PMCID: PMC3583498
View in: PubMed

11.Hart LS, Cunningham JT, Datta T, Dey S, Tameire F, Lehman SL, Qiu B, Zhang H, Cerniglia G, Bi M, Li Y, Gao Y, Liu H, Li C, Maity A, Thomas-Tikhonenko A, Perl AE, Koong A, Fuchs SY, Diehl JA, Mills IG, Ruggero D, Koumenis C. ER stress-mediated autophagy promotes Myc-dependent transformation and tumor growth. J Clin Invest. .122(12):4621-34, 2012. PMCID: PMC3533536
View in: PubMed

12.Gao Y, Sartori DJ, Li C, Yu QC, Kushner JA, Simon MC, Diehl JA. PERK is required in the adult pancreas and is essential for maintenance of glucose homeostasis. Mol Cell Biol. .32(24):5129-39, 2012. PMCID: PMC3510549
View in: PubMed

13.Chitnis NS, Pytel D, Bobrovnikova-Marjon E, Pant D, Zheng H, Maas NL, Frederick B, Kushner JA, Chodosh LA, Koumenis C, Fuchs SY, Diehl JA. miR-211 is a prosurvival microRNA that regulates chop expression in a PERK-dependent manner. Mol Cell. .48(3):353-64, 2012. PMCID: PMC3496065
View in: PubMed

14.Naganuma S, Whelan KA, Natsuizaka M, Kagawa S, Kinugasa H, Chang S, Subramanian H, Rhoades B, Ohashi S, Itoh H, Herlyn M, Diehl JA, Gimotty PA, Klein-Szanto AJ, Nakagawa H. Notch receptor inhibition reveals the importance of cyclin D1 and Wnt signaling in invasive esophageal squamous cell carcinoma. Am J Cancer Res. .2(4):459-75, 2012. PMCID: PMC3410579
View in: PubMed

15.Bobrovnikova-Marjon E, Pytel D, Riese MJ, Vaites LP, Singh N, Koretzky GA, Witze ES, Diehl JA. PERK utilizes intrinsic lipid kinase activity to generate phosphatidic acid, mediate Akt activation, and promote adipocyte differentiation. Mol Cell Biol. .32(12):2268-78, 2012. PMCID: PMC3372262
View in: PubMed

16.Valvezan AJ, Zhang F, Diehl JA, Klein PS. Adenomatous polyposis coli (APC) regulates multiple signaling pathways by enhancing glycogen synthase kinase-3 (GSK-3) activity. J Biol Chem. .287(6):3823-32, 2011. PMCID: PMC3281685
View in: PubMed

17.Schoppy DW, Ragland RL, Gilad O, Shastri N, Peters AA, Murga M, Fernandez-Capetillo O, Diehl JA, Brown EJ. Oncogenic stress sensitizes murine cancers to hypomorphic suppression of ATR. J Clin Invest. .122(1):241-52, 2011. PMCID: PMC3248295
View in: PubMed

18.Vaites LP, Lee EK, Lian Z, Barbash O, Roy D, Wasik M, Klein-Szanto AJ, Rustgi AK, Diehl JA. The Fbx4 tumor suppressor regulates cyclin D1 accumulation and prevents neoplastic transformation. Mol Cell Biol. .31(22):4513-23, 2011. PMCID: PMC3209253
View in: PubMed

19.Ohashi S, Natsuizaka M, Naganuma S, Kagawa S, Kimura S, Itoh H, Kalman RA, Nakagawa M, Darling DS, Basu D, Gimotty PA, Klein-Szanto AJ, Diehl JA, Herlyn M, Nakagawa H. A NOTCH3-mediated squamous cell differentiation program limits expansion of EMT-competent cells that express the ZEB transcription factors. Cancer Res. .71(21):6836-47, 2011. PMCID: PMC3206139
View in: PubMed

20.Aggarwal P, Vaites LP, Kim JK, Mellert H, Gurung B, Nakagawa H, Herlyn M, Hua X, Rustgi AK, McMahon SB, Diehl JA. Nuclear cyclin D1/CDK4 kinase regulates CUL4 expression and triggers neoplastic growth via activation of the PRMT5 methyltransferase. Cancer Cell. .18(4):329-40, 2010. PMCID: PMC2957477
View in: PubMed

21.Bobrovnikova-Marjon E, Hatzivassiliou G, Grigoriadou C, Romero M, Cavener DR, Thompson CB, Diehl JA. PERK-dependent regulation of lipogenesis during mouse mammary gland development and adipocyte differentiation. Proc Natl Acad Sci U S A. .105(42):16314-9, 2008. PMCID: PMC2570995
View in: PubMed

22.Barbash O, Zamfirova P, Lin DI, Chen X, Yang K, Nakagawa H, Lu F, Rustgi AK, Diehl JA. Mutations in Fbx4 inhibit dimerization of the SCF(Fbx4) ligase and contribute to cyclin D1 overexpression in human cancer. Cancer Cell. .14(1):68-78, 2008. PMCID: PMC2597358
View in: PubMed

23.Aggarwal P, Lessie MD, Lin DI, Pontano L, Gladden AB, Nuskey B, Goradia A, Wasik MA, Klein-Szanto AJ, Rustgi AK, Bassing CH, Diehl JA. Nuclear accumulation of cyclin D1 during S phase inhibits Cul4-dependent Cdt1 proteolysis and triggers p53-dependent DNA rereplication. Genes Dev. .21(22):2908-22, 2007. PMCID: PMC2049193
View in: PubMed

24.Lin DI, Barbash O, Kumar KG, Weber JD, Harper JW, Klein-Szanto AJ, Rustgi A, Fuchs SY, Diehl JA. Phosphorylation-dependent ubiquitination of cyclin D1 by the SCF(FBX4-alphaB crystallin) complex. Mol Cell. .24(3):355-66, 2006. PMCID: PMC1702390
View in: PubMed

25.Cullinan SB, Gordan JD, Jin J, Harper JW, Diehl JA. The Keap1-BTB protein is an adaptor that bridges Nrf2 to a Cul3-based E3 ligase: oxidative stress sensing by a Cul3-Keap1 ligase. Mol Cell Biol. .24(19):8477-86, 2004. PMCID: PMC516753
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26.Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA. Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol. .23(20):7198-209, 2003. PMCID: PMC230321
View in: PubMed

27.Brewer JW, Diehl JA. PERK mediates cell-cycle exit during the mammalian unfolded protein response. Proc Natl Acad Sci U S A. .97(23):12625-30, 2000. PMCID: PMC18814
View in: PubMed