Hasem Habelhah, PhD

Portrait
Associate Professor of Pathology

Contact Information

Primary Office: 1173 Medical Laboratories
Iowa City, IA 52242
319-335-6517

Education

BS, Biology, Beijing Normal University
MS, Department of Biology, Beijing Normal University
PhD, Cancer Institute, Hokkaido University School of Medicine

Postdoctoral Fellow, Cancer Institute, Hokkaido University School of Medicine, Sapporo, Japan
Postdoctoral Fellow, D.H. Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, NY

Education/Training Program Affiliations

Interdisciplinary Graduate Program in Molecular Medicine, Medical Scientist Training Program

Center, Program and Institute Affiliations

Holden Comprehensive Cancer Center

Research Summary

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.

Publications

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 TNFa-induced activation of the classic IKK complex in hematopoietic cells in mice. Journal of cell science, 129(7), 1455-67. PMID: 26872784.

Zhang, L., Dittmer, M. R., Blackwell, K., Workman, L. M., Hostager, B. & Habelhah, H. (2015). TRAIL activates JNK and NF-?B through RIP1-dependent and -independent pathways. Cell Signaling, 27(2), 306-14. PMID: 25446254.

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-?B Activation and Lymphoma Survival. Molecular and cellular biology, 35(19), 3324-38. PMID: 26195820.

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-?B 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 I?B kinase activation. Molecular and cellular biology, 33(10), 1901-15. PMID: 23459942.

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.

Shen, R. R., Zhou, A. Y., Kim, E., Lim, E., Habelhah, H. & Hahn, W. C. (2012). I?B kinase e phosphorylates TRAF2 to promote mammary epithelial cell transformation. Molecular and cellular biology, 32(23), :4756-68. PMID: 23007157.

Zhang, L., Blackwell, K., Altaeva, A., Shi, Z. & Habelhah, H. (2011). TRAF2 phosphorylation promotes NF-?B-dependent gene expression and inhibits oxidative stress-induced cell death. Molecular biology of the cell, 22(1), 128-40. PMID: 21119000.

Habelhah, H. (2010). Emerging complexity of protein ubiquitination in the NF-?B pathway. Genes & cancer, 1(7), 735-747. PMID: 21113390.

Zhang, L., Blackwell, K., Shi, Z. & Habelhah, H. (2010). The RING domain of TRAF2 plays an essential role in the inhibition of TNFa-induced cell death but not in the activation of NF-?B. Journal of molecular biology, 396(3), 528-39. PMID: 20064526.

Blackwell, K., Zhang, L., Thomas, G. S., Sun, S., Nakano, H. & Habelhah, H. (2009). TRAF2 phosphorylation modulates tumor necrosis factor alpha-induced gene expression and cell resistance to apoptosis. Molecular and cellular biology, 29(2), 303-14. PMID: 18981220.

Zhang, L., Blackwell, K., Thomas, G. S., Sun, S., Yeh, W. C. & Habelhah, H. (2009). TRAF2 suppresses basal IKK activity in resting cells and TNFa can activate IKK in TRAF2 and TRAF5 double knockout cells. Journal of molecular biology, 389(3), 495-510. PMID: 19409903.

Thomas, G. S., Zhang, L., Blackwell, K. & Habelhah, H. (2009). Phosphorylation of TRAF2 within its RING domain inhibits stress-induced cell death by promoting IKK and suppressing JNK activation. Cancer research, 69(8), 3665-72. PMID: 19336568.

López-Bergami, P., Habelhah, H., Bhoumik, A., Zhang, W., Wang, L. H. & Ronai, Z. (2005). RACK1 mediates activation of JNK by protein kinase C [corrected]. Molecular cell, 19(3), 309-20. PMID: 16061178.

Habelhah, H., Takahashi, S., Cho, S. G., Kadoya, T., Watanabe, T. & Ronai, Z. (2004). Ubiquitination and translocation of TRAF2 is required for activation of JNK but not of p38 or NF-?B. The EMBO journal, 23(2), 322-32. PMID: 14713952.

Habelhah, H., Laine, A., Erdjument-Bromage, H., Tempst, P., Gershwin, M. E., Bowtell, D. D. & Ronai, Z. (2004). Regulation of 2-oxoglutarate (alpha-ketoglutarate) dehydrogenase stability by the RING finger ubiquitin ligase Siah. The Journal of biological chemistry, 279(51), 53782-8. PMID: 15466852.

Habelhah, H., Nakayama, K., Frew, I. J., Hagensen, M., Skals, M., Habelhah, H., Bhoumik, A., Kadoya, T., Erdjument-Bromage, H., Tempst, P., Frappell, P. B., Bowtell, D. D. & Ronai, Z. (2004). Siah2 regulates stability of prolyl-hydroxylases, controls HIF1a abundance, and modulates physiological responses to hypoxia. Cell, 117(7), 941-52. PMID: 15210114.

Habelhah, H., Frew, I. J., Laine, A., Janes, P. W., Relaix, F., Sassoon, D., Bowtell, D. D. & Ronai, Z. (2002). Stress-induced decrease in TRAF2 stability is mediated by Siah2. The EMBO journal, 21(21), 5756-65. PMID: 12411493.

Habelhah, H., Shah, K., Huang, L., Ostareck-Lederer, A., Burlingame, A. L., Shokat, K. M., Hentze, M. W. & Ronai, Z. (2001). ERK phosphorylation drives cytoplasmic accumulation of hnRNP-K and inhibition of mRNA translation. Nature cell biology, 3(3), 325-30. PMID: 11231586.

Minamoto, T., Buschmann, T., Habelhah, H., Matusevich, E., Tahara, H., Boerresen-Dale, A. L., Harris, C., Sidransky, D. & Ronai, Z. (2001). Distinct pattern of p53 phosphorylation in human tumors. Oncogene, 20(26), 3341-7. PMID: 11423984.

Habelhah, H., Shah, K., Huang, L., Burlingame, A. L., Shokat, K. M. & Ronai, Z. (2001). Identification of new JNK substrate using ATP pocket mutant JNK and a corresponding ATP analogue. The Journal of biological chemistry, 276(21), 18090-5. PMID: 11259409.

Yin, Z., Ivanov, V. N., Habelhah, H., Tew, K. & Ronai, Z. (2000). Glutathione S-transferase p elicits protection against H2O2-induced cell death via coordinated regulation of stress kinases. Cancer research, 60(15), 4053-7. PMID: 10945608.

Choi, S., Kobayashi, M., Wang, J., Habelhah, H., Okada, F., Hamada, J., Moriuchi, T., Totsuka, Y. & Hosokawa, M. (2000). Activated leukocyte cell adhesion molecule (ALCAM) and annexin II are involved in the metastatic progression of tumor cells after chemotherapy with Adriamycin. Clinical & experimental metastasis, 18(1), 45-50. PMID: 11206837.

Okada, F., Kawaguchi, T., Habelhah, H., Kobayashi, T., Tazawa, H., Takeichi, N., Kitagawa, T. & Hosokawa, M. (2000). Conversion of human colonic adenoma cells to adenocarcinoma cells through inflammation in nude mice. Laboratory investigation; a journal of technical methods and pathology, 80(11), 1617-28. PMID: 11092522.

Choi, S., Okada, F., Kobayashi, M., Habelhah, H., Nakae, D., Konishi, Y., Totsuka, Y. & Hosokawa, M. (1999). Single treatment with cisplatin or UFT, but not their combination treatment enhances the metastatic capacity of mouse fibrosarcoma cells. Anti-cancer drugs, 10(2), 235-43. PMID: 10211555.

Habelhah, H., Habelhah, H., Okada, F., Kobayashi, M., Nakai, K., Choi, S., Hamada, J., Moriuchi, T., Kaya, M., Yoshida, K., Fujinaga, K. & Hosokawa, M. (1999). Increased E1AF expression in mouse fibrosarcoma promotes metastasis through induction of MT1-MMP expression. Oncogene, 18(9), 1771-6. PMID: 10208438.

Habelhah, H., Okada, F., Nakai, K., Choi, S. K., Hamada, J., Kobayashi, M. & Hosokawa, M. (1998). Polysaccharide K induces Mn superoxide dismutase (Mn-SOD) in tumor tissues and inhibits malignant progression of QR-32 tumor cells: possible roles of interferon alpha, tumor necrosis factor-a and transforming growth factor-ß in Mn-SOD induction by polysaccharide K. Cancer immunology, immunotherapy, 46(6), 338-44. PMID: 9756418.

Hornick, E. A., McGill, J. L. & Legge, K. L. Chronic ethanol exposure selectively inhibits the influenza-specific CD8 T cell response during influenza a virus infection. Alcoholism, clinical and experimental research, 38(9), 2403-13. PMID: 25160044.

Habelhah, H. (1998). [Induction of manganese superoxide dismutase by an immunopotentiator as a mechanism of inhibiting of malignant progression of murine tumor cells]. [Hokkaido igaku zasshi] The Hokkaido journal of medical science, 73(5), 519-29. PMID: 9846281.