Hasem Habelhah, PhD
Introduction
My laboratory has a long-standing interest in understanding the molecular mechanisms by which inflammatory cytokines and cellular stresses activate the NF-kB pathway. NF-kB is a transcription factor that induces the expression of more than 300 genes that regulate cell growth, survival and motility, and is constitutive activated in many types of inflammatory diseases and cancer. However, targeting the core elements of the NF-kB pathway (e.g. TAK1, IKK and p65) for treatment of human diseases has failed repeatedly, due to severe side effects associated with immune suppression and disruption of epithelial homeostasis. TRAF2 and RIP1 are key effector proteins that are required for the activation of the TAK1/IKK/NF-kB pathway. We mapped TRAF2 phosphorylation and RIP1 cleavage sites that play critical roles in cytokine- and cellular stress-induced NF-kB activation. We are currently characterizing the molecular mechanisms by which TRAF2 phosphorylation and RIP1 cleavage regulate NF-kB activation. Our long-term goal is to identify cell type- and disease-specific effectors upstream of the TAK1/IKK/NF-kB axis that lead to constitutive NF-kB activation in inflammatory diseases and cancers, and to provide a foundation for the development of pathway-specific anti-inflammatory and anti-cancer drugs.
Current Positions
- Associate Professor of Pathology
Education
- BS in Biology, Beijing Normal University, Beijing, China
- MS in Department of Biology, Beijing Normal University, China
- PhD in Cancer Institute, Hokkaido University School of Medicine, Sapporo, Japan
- Postdoctoral Fellow in Cancer Institute, Hokkaido University School of Medicine, Sapporo, Japan
- Postdoctoral Fellow in D.H. Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, NY
Graduate Program Affiliations
Center, Program and Institute Affiliations
Research Interests
- The role of TRAF2 phosphorylation in TNFR1 and CD40 signaling
- Examine the effect of indomethacin on intestinal motility in sheep
- HtrA2-mediated RIP1 cleavage regulates neuronal inflammation and death
- ERK phosphorylation drives cytoplasmic accumulation of hnRNP-K and subsequent inhibition of mRNA translation
- ERK phosphorylation drives cytoplasmic accumulation of hnRNP-K and subsequent inhibition of mRNA translation
- Polysaccharide K induces inhibits malignant progression of QR-32 tumor cells by modulating expression of Mn-SOD
- The role of TRAF2 phosphorylation in cancer cell adaptation to chronic ER stress
- Therapeutic efficacy of combined inhibition of AKT and TBK1 in breast cancer (BC)
Selected Publications
- Miao, J., Xu, M., Kuang, Y., Pan, S., Hou, J., Cao, P., Duan, X., Chang, Y., Hasem, H., Zhou, N., Tan, K. & Fan, Y. (2020). Deferasirox protects against hydrogen peroxide-induced cell apoptosis by inhibiting ubiquitination and degradation of p21WAF1/CIP1. Biochemical and biophysical research communications 524 (3) 736-743. DOI: 10.1016/j.bbrc.2020.01.155. PMID: 32035614.
- Workman, L. M., Zhang, L., Fan, Y., Zhang, W. & Habelhah, H. (2020). TRAF2 Ser-11 phosphorylation promotes cytosolic translocation of the CD40 complex to regulate downstream signaling pathways. Molecular and cellular biology. DOI: 10.1128/MCB.00429-19. PMID: 32041822.
- Xiu, Y., Dong, Q., Fu, L., Bossler, A., Tang, X., Boyce, B., Borcherding, N., Leidinger, M., Sardina, J. L., Xue, H. H., Li, Q., Feldman, A., Aifantis, I., Boccalatte, F., Wang, L., Jin, M., Khoury, J., Wang, W., Hu, S., Yuan, Y., Wang, E., Yuan, J., Janz, S., Colgan, J., Habelhah, H., Waldschmidt, T., Müschen, M., Bagg, A., Darbro, B. & Zhao, C. (2019). Coactivation of NF-κB and Notch signaling is sufficient to induce B cell transformation and enables B-myeloid conversion. Blood. DOI: 10.1182/blood.2019001438. PMID: 31697816.
- Franqui-Machin, R., Hao, M., Bai, H., Gu, Z., Zhan, X., Habelhah, H., Jethava, Y., Qiu, L., Frech, I., Tricot, G. & Zhan, F. (2018). Destabilizing NEK2 overcomes resistance to proteasome inhibition in multiple myeloma. The Journal of clinical investigation. DOI: 10.1172/JCI98765. PMID: 29863498.
- Zhang, L., Blackwell, K., Workman, L. M., Gibson-Corley, K. N., Olivier, A. K., Bishop, G. A. & Habelhah, H. (2016). TRAF2 exerts opposing effects on basal and TNFα-induced activation of the classic IKK complex in hematopoietic cells in mice. Journal of cell science 129 (7) 1455-67. DOI: 10.1242/jcs.180554. PMID: 26872784.
- Zhang, L., Blackwell, K., Workman, L. M., Chen, S., Pope, M. R., Janz, S. & Habelhah, H. (2015). RIP1 Cleavage in the Kinase Domain Regulates TRAIL-Induced NF-κB Activation and Lymphoma Survival. Molecular and cellular biology 35 (19) 3324-38. DOI: 10.1128/MCB.00692-15. PMID: 26195820.
- Zhang, L., Dittmer, M. R., Blackwell, K., Workman, L. M., Hostager, B. & Habelhah, H. (2015). TRAIL activates JNK and NF-κB through RIP1-dependent and -independent pathways. Cell Signaling 27 (2) 306-14. PMID: 25446254.
- Hadweh, P., Habelhah, H., Kieff, E., Mosialos, G. & Hatzivassiliou, E. (2014). The PP4R1 subunit of protein phosphatase PP4 targets TRAF2 and TRAF6 to mediate inhibition of NF-κB activation. Cell Signaling 26 (12) 2730-7. PMID: 25134449.
- Blackwell, K., Zhang, L., Workman, L., Ting, A., Iwai, K. & Habelhah, H. (2013). Two coordinated mechanisms underlie tumor necrosis factor alpha-induced immediate and delayed IκB kinase activation. Molecular and cellular biology 33 (10) 1901-15. PMID: 23459942. PMCID: PMC3647962.
- Workman, L. M. & Habelhah, H. (2013). TNFR1 signaling kinetics: spatiotemporal control of three phases of IKK activation by posttranslational modification. Cellular signalling 25 (8) 1654-64. PMID: 23612498. PMCID: PMC3824607.