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 necessary framework 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. 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 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 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. 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 PERK regulates Akt and cell survival and assess the feasibility of targeting PERK as a means of treating specific cancers.
The Diehl laboratory focuses on the investigation of the basic mechanisms that drive neoplastic growth and tumor cell survival. Using state-of-the-art techniques, including genomics, proteomics, and mouse models, our group has identified novel molecular targets that function as key drivers of neoplastic growth in a variety of cancer etiologies. Through the investigation of these pathways, the Diehl lab is driven to not only provide new insights into the mechanisms of cancer as a disease, but also to develop new therapeutic modalities to combat tumorigenesis.
01. 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 SCFFBX4-aBcrystallin complex. Molecular Cell. 24:355-366, 2006.
02. Bobrovnikova-Marjon E, Hatzivassiliou G, Grigoriadou C, Romero M, Cavener D, Thompson CB and Diehl JA. PERK-dependent regulation of lipogenesis during mammary gland development. Proceedings of the National Academy of Sciences USA 105:16314-16319, 2008.
03. 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.
04. Zeng Z, Wang W, Yang Y, Chen Y, Yang X, Li Y, Hao B, Diehl JA, Liu X, Lei M. Structural Basis of Selective Ubiquitination TRF1 by SCFFBX4 . Developmental Cell. 18:214-225, 2010.
05. Aggarwal P, Pontano Vaites L, Kim JK, Mellert H, Gurang B, Hua X, Nakagawa H, Herlyn M, Rustgi AK, McMahon SB and Diehl JA. Nuclear Cyclin D1/CDK4 Kinase Regulates Cul4 Expression and Genomic Instability via Activation of the PRMT5 Methyltransferase. Cancer Cell. Oct 19;18(4):329-40, 2010.
06. 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. (22):4513-23. 2011.
07. Bobrovnikova-Marjon E, Pytel D, Vaites LP, Singh N, Diehl JA. PERK utilizes intrinsic lipid kinase activity to mediate Akt activation and adipocyte differentiation. Mol Cell Biol. 32:2268-78. 2012. Highlighted: Sci Signaling, May 29, 2012.
08. Gao Y, Sartori DJ, Li C, Yu Q-C, Kushner JA, Diehl JA. PERK is required in the adult pancreas and essential for maintenance of glucose homeostasis. Mol Cell Biol 24:5129-5139 2012. Highlighted in the “Spotlights of the Current Issue”.
09. Vaites LP, Lian Z, Yin B, DeMicco A, Bassing CH, Diehl JA. ATM deficiency augments constitutively nuclear cyclin D1-driven genomic instability and lymphomagenesis. In Press. Oncogene. 2012.
10. Chitnis N, Pytel D. Bobrovnikova-Marjon E, Pant D, Zheng H, Maas N, Frederick B, Kushner JA, Chodosh LA, Koumenis C, Fuchs SY, Diehl JA. miR-211 is a pro-survival micro-RNA that regulates chop expression in a PERK-dependent manner. Mol Cell. 48(3):353-364. 2012. Highlighted: Nature Cell Biology Nov 14(11):1129.
Akihiro Yoshida - Postdoctoral Researcher
Dariusz Pytel - Postdoctoral Researcher
Erin Quinn - Administrative Assistant
Lukasz Markiewicz - Visiting Fullbright Scholar
Margarita Romero - Lab Manager/Research Technician
Nilesh Chitnis - Postdoctoral Researcher
Yan Gao - Postdoctoral Researcher
Yan Li - Postdoctoral Researcher
Zhaorui Lian - Research Specialist
Zhenhua Xu - Postdoctoral Researcher
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