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J. Alan Diehl, Ph.D.

J. Samuel Staub, M.D. Endowed Professor
Associate Investigator, The Leonard and Madlyn Abramson Family Cancer Research Institute, University of Pennsylvania
Director, Cancer Cell Biology Program, The Leonard and Madlyn Abramson Family Cancer Research Institute, University of Pennsylvania
Director, Cancer Cell Biology Program , Abramson Family Cancer Research Institute
Co-Director, Tumor Biology, Abramson Cancer Center
Department: Cancer Biology

Contact information
413 Biomedical Research Bldg. II/III
421 Curie Boulevard
Philadelphia, PA 19104-6160
Office: 215-746-6389
Fax: (215) 746-5525
Education:
B.S. (Summa cum Laude; Biochemistry )
North Carolina State University, Raleigh, North Carolina , 1990.
Ph.D. (Biochemistry)
University of Missouri-Columbia, Columbia, Missouri , 1995.
Post-Graduate Training
Research Associate, Howard Hughes Medical Institute, Department of Tumor Cell Biology , St. Jude Children's Research Hospital, Memphis, TN , 1995-1999.
Postdoctoral Associate, Department of Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee, 1999-1999.
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Description of Research Expertise

Research Interests
Cell cycle regulation in normal versus cancer cells; Checkpoint signaling as it pertains to cancer progression.

Key words: Cyclin D1, CDK4, Cancer, Nuclear export, oncogene, Unfolded protein response, PERK, Akt.

Description of Research
My laboratory focuses on the mechanisms whereby extra-cellular signals are sensed by the cell cycle machine and are then transmitted into regulated cell cycle progression. This information will provide the framework necessary to elucidate how growth regulatory pathways are subverted during neoplasia. One major focus concerns the elucidation of 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. Recently, we have identified a novel alternatively spliced cyclin D1 isoform whose expression is restricted to cancer cells. Our data suggests that this cyclin D1 isoform may be refractory to normal growth factor signals and play a causative role in the neoplastic process.

A second area of interest concerns how a novel stress-induced signaling pathway emanating from the endoplasmic reticulum (ER) regulates cell cycle progression 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 limiting 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, Ire1?, and Ire1?) 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. My lab has recently 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. The objectives of our current work have been to identify and characterize the mechanisms whereby the PERK kinase contributes to cell survival and thus tumor development.

Rotation Projects
Please contact Dr. Diehl to discuss potential rotation projects.

Lab personnel:
Nilesh Chitnish, Postdoctoral Researcher
Brian Frederick, Graduate Student
Yan Gao, Postdoctoral Researcher
Sanjeev Kumar, Postdoctoral Researcher
Eric Lee, Graduate Student
Yan Li, Postdoctoral Researcher
Laura Pontano Vaites, Graduate Student
Dariusz Pytel, Postdoctoral Researcher
Margarita Romero, Research Specialist and Lab Manager
Erin Quinn, Administrative Coordinator

Selected Publications

Hamanaka RB, Bobrovnikova-Marjon E, Ji X, Liebhaber SA, Diehl JA: PERK-dependent regulation of IAP translation during ER stress. Oncogene 28(6): 910-20, February 2009 Notes: Epub 2008 Nov 24.

Pontano LL, Aggarwal P, Barbash O, Brown EJ, Bassing CH, Diehl JA: Genotoxic stress-induced cyclin D1 phosphorylation and proteolysis are required for genomic stability. Molecular and Cellular Biology 28(23): 7245-58, December 2008 Notes: Epub 2008 Sep 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, July 2008.

Bobrovnikova-Marjon E, Hatzivassiliou G, Grigoriadou C, Romero M, Cavener DR, Thompson CB, Diehl JA: PERK-dependent regulationof lipogenesis during mouse mammary gland development and adipocyte differentiation. Proceedings of the National Academy of Sciences of the United States of America 105(42): 16314-9, October 2008 Notes: Epub 2008 Oct 13.

Lin DI, Aggarwal P, Diehl JA : Phosphorylation of MCM3 on Ser-112 regulates its incorporation into the MCM2-7 complex. Proceedings of the National Academy of Sciences of the United States of America 105(23): 8079 - 8084, June 2008.

Aggarwal P, Lessie M, Lin DI, Pontano L, Gladden AB, Nuskey B, Goradia A, Wasik MA, Klein-Szanto AJP, Rustgi AK, Bassing CH, Diehl JA: Nuclear accumulation of cyclin D1 during S-phase inhibits Cdt1 proteolysis and triggers p53-dependent DNA re-replication. Genes & Development 21: 2908-2922 November 2007.

Lin DI, Barbash O, Kumar KG, Weber JD, Harper JW, Klein-Szanto AJP, Rustgi A, Fuchs SY, Diehl JA: Phosphorylation-dependent ubiquitination of cyclin D1 by the SCF (FBX4-alphaB crystallin) complex. Molecular Cell 24(3): 355-366 November 2006.

Bobrovnikova-Marjon E, Diehl JA: Coping with stress: ATF6 takes the stage. Developmental Cell 13: 322-324, September 2007.

Gladden AB, Woolery R, Aggarwal P, Wasik MA, Diehl JA: Expression of constitutively nuclear cyclin D1 in murine lymphocytes induces B-cell lymphoma. Oncogene 25: 998-1007 February 2006.

Zhang F, Hamanaka RB, Bobrovnikova-Marjon E, Gordan J, Dai MS, Lu H, Simon MC, Diehl JA: Ribosomal stress couples the unfolded protein response to p53-dependent cell cycle arrest. Journal of Biological Chemistry 281: 30036-30045, October 2006.

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Last updated: 11/01/2013
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