1157 Medical Laboratories
500 Newton Road
University of Iowa
Iowa City, IA 52242-1109
BS, Biological Sciences, University of Missouri
BA, Political Science, University of Missouri
My research interest focuses on study of inflammation-mediated tumorigenesis and its role in malignant progression. TNF-receptor associated factor 2 (TRAF2) is a RING domain-containing adaptor protein that transduces signals emanating from several TNF-Receptor superfamily members. Using a classical phospho-peptide mapping approach, our lab identified two phosphorylation sites in the TRAF2 N-terminus (Ser-11 and Ser-55) that promote TNFα- and CD40L-induced JNK and NF-κB activation.
My project is to define the role of TRAF2 phosphorylation in regulating the CD40 receptor signaling kinetics and its participation in neoplastic B cell survival. The CD40L/CD40 costimulatory interaction results in JNK/c-Jun and IKK/NF-κB pathway activation that promotes B cell proliferation, differentiation, and survival necessary for a robust adaptive immune response; however, the mechanisms by which these signaling pathways are initially activated remains unclear. Constitutive CD40 pathway activation has also been shown to promote the progression and therapeutic resistance of B cell-derived malignancies by potentiating sustained NF-κB activation. This results in the increased expression of anti-apoptotic factors that protect malignant cells from death receptor- and chronic stress-induced cell death. Since the tumor microenvironment is characterized by hypoxia, low glucose, and free radicals that induce chronic cellular stress, cancer cell adaptation to these stressors has profound consequences for malignant progression and therapeutic response. TRAF2 can be found over-expressed and constitutively phosphorylated in a majority of B cell-derived cancer cell lines and primary tumor samples, suggesting that it may serve as a mechanism responsible for the elevated NF-κB activation and apoptotic resistance observed in B cell-derived neoplasms and a relevant molecular target for future therapies.
- LM Workman, K Blackwell, LQ Zhang, BS Hostager, GA Bishop, and H Habelhah. TRAF2 phosphorylation controls the CD40-mediated spatiotemporal activation of the NF-κB and JNK pathways to promote neoplastic B cell survival. 14th International TNF Conference. Quebec City, Canada. Oral presentation, 2013.
- Workman LM, Habelhah H. TNFR1 Signaling Kinetics: Spatiotemporal control of three phases of IKK activation by post-translational modification. Cellular Signaling, 2013. PMID: 23612498
- Blackwell K, Zhang L, Workman LM, Ting AT, Iwai K, Habelhah H. Two coordinated mechanisms underlie TNFα-induced immediate and delayed IKK activation. Molecular and Cellular Biology, 2013. PMID: 23459942.
- Habelhah H, Zhang LQ, Blackwell K, Workman LM. cFLIP-regulated and caspase-8-mediated limited cleavage of RIP1 promotes NF-κB activation and inhibits cell death induced by TRAIL. 103rd Annual Meeting of American Association for Cancer Research. Chicago, IL. Oral presentation, 2012.
- Zhang LQ, Blackwell K, Workman LM, Habelhah H. TNFα activates NF-κB through RIP1 ubiquitination- dependent and independent pathways. 103rd Annual Meeting of American Association for Cancer Research. Chicago, IL. Poster presentation, 2012.
- Workman LM, Blackwell K, Zhang L, Bishop G, Habelhah H. TRAF2 phosphorylation on Serine-11 regulates CD40-induced JNK and NF-κB activation. Keystone Symposia: NF-κB Signaling and Biology: From Bench to Bedside. Whistler, BC. Poster presentation, 2012.
Awards, Honors, Activities
- Scientists’ Survival Skills Committee, 2012-2013
- MCB Seminar Committee, 2012-2014
- Holden Comprehensive Cancer Center Trainee, 2013-2016