PROJECT 2 ABSTRACT The long-term objective of this Project centers on elucidation of the mechanisms whereby extra-cellular signals are sensed by the cell cycle machinery and regulate cell cycle progression during neoplastic conversion of epithelium. Our current work focus on the mitogenically responsive D-type cyclin, cyclin D1, and more specifically how the aberrant accumulation of cyclin D1 contributes to esophageal cancers and whether our enhanced understanding of cyclin D1 regulation can contribute to new and more effective therapies for this deadly disease. Progress in the characterization of the mechanism of cyclin D1 overexpression in cancer has been hindered by lack of information regarding the nature of the E3 ubiquitin ligase that directs cyclin D1 proteolysis. We have identified the SCF (FBX4-?B crystallin) that controls cyclin D1 ubiquitination and degradation in esophageal cancer. Importantly, the progress we have made during the past 5 years has provided key insights into the mechanisms whereby dysregulated cyclin D/CDK4 activity contributes to the neoplastic conversion of a normal cell and to the ongoing proliferation and survival of esophageal tumor clones. This progress now provides a framework critical for proper utilization, evaluation and interpretation of the effects that can be achieved by treatment of cancer patients with the evolution of highly specific small molecule inhibitors of the cyclin D1/CDK4 kinase. Having developed this framework describing mechanisms of cyclin D1 dysregulation in esophageal cancer (in particular, esophageal squamous cell cancer or ESCC), we are now in an ideal position to translate these novel concepts and in doing so develop effective therapies for a cancer lacking in any significant therapeutic intervention. As direct result of this progress, we now propose an overarching new hypothesis wherein the SCFFBX4-?B crystallin E3 ligase maintains threshold levels of the cyclin D1/CDK4 kinase critical for esophageal cell growth and homeostasis. We further hypothesize that therapeutic strategies targeting the cyclin D1/CDK4 kinase, or key downstream effectors (such as PRMT5), could be of significant therapeutic benefit in the treatment of esophageal cancer. Experiments proposed in this grant will directly determine the physiological contribution of Fbxo4 to the regulation of cyclin D1 accumulation and neoplastic activity in esophageal epithelium (Aim 1);assess the therapeutic efficacy of targeting the catalytic partner for cyclin D1 (CDK4/6) in esophageal cancer (Aim 2);and finally, address the mechanistic contributions of the histone methyltransferase, PRMT5, to the neoplastic activities of cyclin D1/CDK4 in esophageal cancer (Aim 3). Collectively, this unified approach is utilizing mechanistic findings as a platform for new translational/therapeutic strategies in ESCC that have potential applicability to other related cancers, such as head/neck squamous and lung squamous cell cancers. Our mechanistic approaches and translational applications are unified by integrated and synergistic approached with Projects 1 and 3, all supported by the Core Facilities.

Public Health Relevance

PROJECT 2 NARRATIVE Overexpression of cyclin D1 in human esophageal cancer occurs frequently as a consequence of mutations in the machinery that destroys the cyclin D1 protein. In order to develop effective therapies that counter these events, we have identified the critical component of the machinery, Fbxo4, which directs destruction of the cyclin D1 protein. The experiments described in this proposal will evaluate the biological properties of Fbxo4 in esophageal cancer and determine the efficacy of therapeutic approaches that inhibit the catalytic function of cyclin D1CDK4.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA098101-11
Application #
8741116
Study Section
Special Emphasis Panel (ZCA1-RPRB-O (M1))
Project Start
2002-12-01
Project End
2019-06-30
Budget Start
2014-08-01
Budget End
2015-06-30
Support Year
11
Fiscal Year
2014
Total Cost
$287,668
Indirect Cost
$81,331
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Tetreault, Marie-Pier; Weinblatt, Daniel; Shaverdashvili, Khvaramze et al. (2016) KLF4 transcriptionally activates non-canonical WNT5A to control epithelial stratification. Sci Rep 6:26130
Yoshida, Akihiro; Lee, Eric K; Diehl, J Alan (2016) Induction of Therapeutic Senescence in Vemurafenib-Resistant Melanoma by Extended Inhibition of CDK4/6. Cancer Res 76:2990-3002
Kong, Jianping; Whelan, Kelly A; Laczkó, Dorottya et al. (2016) Autophagy levels are elevated in barrett's esophagus and promote cell survival from acid and oxidative stress. Mol Carcinog 55:1526-1541
Dotto, G Paolo; Rustgi, Anil K (2016) Squamous Cell Cancers: A Unified Perspective on Biology and Genetics. Cancer Cell 29:622-37
Qie, Shuo; Diehl, J Alan (2016) Cyclin D1, cancer progression, and opportunities in cancer treatment. J Mol Med (Berl) 94:1313-1326
Tétreault, Marie-Pier; Weinblatt, Daniel; Ciolino, Jody Dyan et al. (2016) Esophageal Expression of Active IκB Kinase-β in Mice Up-Regulates Tumor Necrosis Factor and Granulocyte-Macrophage Colony-Stimulating Factor, Promoting Inflammation and Angiogenesis. Gastroenterology 150:1609-1619.e11
Whelan, Kelly A; Merves, Jamie F; Giroux, Veronique et al. (2016) Autophagy mediates epithelial cytoprotection in eosinophilic oesophagitis. Gut :
Lin, E W; Karakasheva, T A; Hicks, P D et al. (2016) The tumor microenvironment in esophageal cancer. Oncogene 35:5337-5349
Shearin, Abigail L; Monks, Bobby R; Seale, Patrick et al. (2016) Lack of AKT in adipocytes causes severe lipodystrophy. Mol Metab 5:472-9
Facompre, Nicole D; Harmeyer, Kayla M; Sole, Xavier et al. (2016) JARID1B Enables Transit between Distinct States of the Stem-like Cell Population in Oral Cancers. Cancer Res 76:5538-49

Showing the most recent 10 out of 139 publications