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.