Department of biochemistry and Molecular biology
J. Alan Diehl, PhD
2013-2014 J. Samuel Staub Endowed Professor, University of Pennsylvania
2009-2014 Professor, Department of Cancer Biology, University of Pennsylvania
Investigator, The Abramson Family Cancer Research Institute
2007-2014 Director, Cancer Cell Biology Program, The Abramson Family Cancer Research Institute
2005-2009 Associate Professor, Department of Cancer Biology, University of Pennsylvania
Investigator, The Abramson Family Cancer Research Institute
2001-2005 Assistant Professor, Department of Cancer Biology, University of Pennsylvania
Assistant Investigator, The Abramson Family Cancer Research Institute
1999-2001 Assistant Professor, The Epply Institute for Cancer and Allied Disease, University of Nebraska Medical Center
1995-1999 Research Associate, Howard Hughes Medical Institute, Department of Tumor Cell Biology / St. Jude Children's Research Hospital
1995 Ph.D., Biochemistry, University of Missouri
1990 B.S., Biochemistry, North Carolina State University, Raleigh
Office: HCC-712F / 843-792-1449
Lab: HCC-709 / 843-792-6837
86 Jonathan Lucas Street
Hollings Cancer Center, Charleston, SC 29425
The Diehl lab focuses on the mechanisms whereby extra-cellular signals are sensed by the cell cycle machine and are then transmitted into regulated cell cycle progression. Elucidation of these mechanisms provides a framework wherein we can understand and interrogate growth regulatory pathways that are subverted during tumor development and progression. One major focus of the laboratory concerns the mechanisms whereby growth-signaling pathways regulate the mitogenically responsive D-type cyclins and more specifically, how these pathways regulate accumulation of an active, nuclear cyclin D1-dependent kinase. Our current work focuses on the role of E3 ubiquitin ligases in the maintenance of cyclin D1 levels and the physiological function of the E3 ligase in tumor suppression. Additional work focuses on the regulation of novel downstream substrates of the cyclin D1/CDK4 kinase and their role in mediating cyclin D1-dependent effects on tumor cell gene expression networks.
A second area of interest concerns how a stress-induced signaling pathway emanating from the endoplasmic reticulum (ER) regulates cell cycle progression, lipid biosynthesis and cell survival during tumor progression. The initial rapid expansion of tumor cells can result in a microenvironment wherein metabolic nutrients such as glucose, oxygen, and growth factors become limited as cellular volume expands beyond the established vascularity of the tissue. The endoplasmic reticulum is acutely sensitive to limiting levels of glucose and oxygen and thus functions as an early “sensor” for these cellular nutrients. Mammalian cells contain three distinct ER transmembrane protein kinases (PERK, Ire1α, and Ire1β) that function as proximal effectors that are activated upon nutrient deprivation. These protein kinases coordinate the induction of ER chaperones, suppress protein synthesis, inhibit cell cycle progression, and promote apoptotic cell death. The Diehl laboratory has previously demonstrated that PERK mediates UPR-induced cell cycle arrest via inhibition of cyclin D1 protein synthesis. PERK also contributes to cellular adaptation via activation of a gene expression program that is dependent upon anti-oxidant signaling and Akt activation. More recently, the Diehl laboratory has identified micro-RNAs that are responsive to ER stress. Elucidating the targets and biological significance of these miRNAs with regard to tumor progression is currently a major focus.
Recent Publications | Additional Publications
Katlinskaya YV, Katlinski KV, Qiujing Y, Ortiz A, Beiting DP, Brice A, Davar D, Sanders C, Kirkwood JM Rui H, Xu X, Koumenis C, Diehl JA, Fuchs SY. (2016) Suppression of type I interferon signaling overcomes the oncogene-induced senesce and mediates melanoma development and progression. Cell Rep, in press.
Cárdenas C, Müller M, McNeal A, Lovy A, Jaňa F, Bustos G, Urra F, Smith N, Molgó J, Diehl JA, Ridky TW, Foskett JK. (2016) Selective vulnerability of cancer cells by inhibition of Ca2+ transfer from the endoplasmic reticulum to mitochondria. Cell Rep 14(10):2313-24. PMID: 26947070
Yoshida A, Lee EK, Diehl JA. (2016) Induction of therapeutic senescence in vemurafenib-resistant melanoma by extended inhibition of CDK4/6. Cancer Research, in press. pii: canres.2931.2015. [Epub ahead of print]
Xu Z, Bu Y, Chitnis N, Koumenis CK, Fuchs SY, Diehl JA. (2016) miR-216b regulation of c-Jun mediates GADD153/CHOP-dependent apoptosis. Nature Communications, in press.
Xie W, Pariollaud M, Wixted WE, Chitnis N, Fornwald J, Truong M, Pao C, Liu Y, Ames RS, Callahan J,Solari R, Sanchez, Y, Diehl JA, Hu Li H. (2015) Identification and characterization of PERK activators by phenotypic screening and their effects on NRF2 activation. PLoS One 10(3):e0119738.
Qiu B, Ackerman D, Sanchez DJ, Li B, Ochocki JD, Grazioli A, Bobrovnikova-Marjon E, Diehl JA, Keith B, Simon MC. (2015) HIF-2α dependent lipid storage promotes endoplasmic reticulum homeostasis in clear cell renal cell carcinoma. Cancer Discovery 5:652-667.
Lian Z, Lee EK, Bass AJ, Won KK, Klein-Szanto AJP, Rustgi AK, Diehl JA. (2015) FBXO4 loss facilitates carcinogen induced papilloma development in mice. Cancer Biol Ther 16(5):750-5.
Augello MA, Berman-Booty LD, Carr R 3rd, Yoshida A, Dean JL, Schiewer MJ, Feng FY, Tomlins SA, Gao E, Koch WJ, Benovic JL, Diehl JA, Knudsen KE. (2015) Consequence of the tumor associated conversion to cyclin D1b. EMBO Mol Med 7(5):628-47.
Yu Q, Zhao B, Gui J, Katlinski KV, Brice A, Gao Y, Li C, Kushner JA, Koumenis C, Diehl JA, Fuchs SY. (2015) Type I interferons mediate pancreatic toxicities of PERK inhibition. Proc Natl Acad Sci USA 112(50):15420-5.
Dey, S, Sayers CM, Lehman SL, Cheng Y, Cerniglia G, Tuttle SW, Fuchs SY, Diehl JA, Koumenis C. (2015) ATF4-dependent induction of heme oxygenase 1 prevents anoikis and promotes metastasis. J Clin Invest 125:2592-2608. PMID:260116422015
Li Y, Chitnis N, Nakagawa H, Kita Y, Natsugoe S, Yang Y, Li Z, Wasik M, Klein-Szanto APJ, Rustgi AK, Diehl JA. (2015) PRMT5 is required for lymphomagenesis triggered by multiple oncogenic drivers. Cancer Discovery 5:288-303.
Vaites LP, Lian Z, Yin B, DeMicco A, Bassing CH, Diehl JA.(2014) ATM deficiency augments constitutively nuclear cyclin D1-driven genomic instability and lymphomagenesis. Oncogene 33:129-133.
Bu Y and Diehl JA. (2016) PERK integrates oncogenic signaling and cell survival during cancer development. J Cell Physiol doi: 10.1002/jcp.25336. [Epub ahead of print]
Rozpędek W, Markiewicz Ł, Diehl JA, Pytel D, Majsterek I. (2015) The role of the adaptive stress response in the pathogenesis of neurodegenerative diseases, cancer and diabetes mellitus type 2. Pol Merkur Lekarski 39:393-397.
Rozpędek W, Markiewicz L, Diehl JA, Pytel D, Majsterek I. (2015) Unfolded protein response and PERK kinase as a new therapeutic target in the pathogenesis of Alzheimer's disease. Curr Med Chem 22(27):3169-84.
Yoshida A and Diehl JA. (2015) CDK4/6 inhibitor as a therapeutic regulator of a transition between quiescence and senescence. Oncoscience 2:896-897.
Maas NL and Diehl JA. (2015) Molecular pathways: The PERKs and pitfalls of targeting the unfolded protein response in cancer. Clinical Cancer Research 21:675-679.
Li Y and Diehl JA. (2015) PRMT5-dependent p53 escape in tumorigenesis. Oncoscience 2(8):700-2.
Pytel D, Majsterek I, Diehl JA. (2015) Tumor progression and the different faces of the PERK kinase. Oncogene doi: 10.1038/onc.2015.178. [Epub ahead of print]