J. Alan Diehl
Program Director, Cancer Cell Biology
Associate Professor & Associate Investigator, Abramson Family Cancer Research Institute; Depts of Cancer Biology; Cell and Developmental Biology

Cancer Biology Program

Address

454 Biomedical Rsch Bldg (BRB) II/III
421 Curie Boulevard
Philadelphia, PA 19104-6140

Office tel.: 215 746-6389
Lab tel.: 215 746-6388
Fax: 215 746-5511
E-mail: adiehl@mail.med.upenn.edu

Link(s)

Dr. Diehl's Abramson Family Cancer Research Institute Webpage

Education

North Carolina State University: BS (Biochemistry), 1990.

University of Missouri: PhD (Biochemistry), 1995.

St. Jude Children’s Research Hospital: Postdoctoral Research (Tumor Cell Biology and Cell Cycle Regulation), 1995-1999.

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, Nrf2.

Description fo 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, 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. 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 the Nrf2 pro-survival transcription factor. 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.

Selected Publications

Hamanaka, RB, Bennett, BS, Cullinan, SB, Diehl JA. PERK and GCN2 contribute to eIF2alpha phosphorylation and cell cycle arrest following activation of the Unfolded Protein Response Pathway. Mol Biol Cell. 16:5493-5501. 2005.

Bobrovnikova-Marjon E and Diehl JA. Coping with Stress: ATF6 takes the stage. Dev Cell 13:322-324. 2007.

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 & Dev. 21: 2908-2922. 2007.

Lin DI, Aggarwal P and Diehl JA. Phosphorylation of MCM3 on Ser112 Regulates its Incorporation into the MCM2-7 Helicase. PNAS. 105:8079-8084 2008.

Barbash O, Zamfirova P, Lin DI, Lu F, Nakagawa H, Rustgi AK and Diehl JA. Mutations in Fbx4 inhibit phosphorylation-dependent dimerization of the SCFFbx4 ligase and contribute to cyclin D1 overexpression in human cancer. Cancer Cell. 4:68-78. 2008.

Search PubMed for more articles

Lab

Rotation Projects

Lab personnel

Olena Barbash Postdoctoral Researcher
Ekaterina Bobrovnikova-Marjon, Postdoctoral Researcher
Priya Aggarwal, Postdoctoral Researcher
Nilesh Chitnis, Postdoctoral Researcher
Dariusz Pytel, Postdoctoral Researcher
Laura Pontano, Graduate Student
Margarita Romero, Research Specialist/Lab Manager
Petia Zamfirova, Research Specialist
Shivani Sethi, Admin. Coordinator