Hassel Lab Research Interests

Bret Hassel, Ph.D.

Hassel Lab Research Interests:

   Control of cell proliferation is essential for the proper development and differentiation of multicellular organisms and is achieved through the precise regulation of growth stimulatory and growth inhibitory pathways. Perturbations in the balance of these processes can result in pathologic conditions including cancer. The interferons (IFNs) were among the first characterized growth inhibitory cytokines, and are now known to induce growth arrest or cell death, depending on the cellular context. A similar cytostatic/pro-apoptotic dichotomy is observed in response to genotoxic agents, illustrating a striking parallel in the cellular outcome of diverse stresses. The altered pattern of gene expression in cancer cells often results in a differential response to stress when compared to normal cells. To best exploit this differential response, and enhance the efficacy of anti-neoplastic agents, it is essential to identify key molecular mediators of the stress response. Towards this end, we seek to understand the nature of the cellular sensors of stress, the signaling pathways activated by these sensors, and the regulation and function of target genes in mediating the stress response.

    We have demonstrated that a common set of signaling pathways and target genes are activated by diverse stress agents, suggesting that crosstalk between these pathways is important in mediating the cellular response. Specifically, we have identified two genes, ISG15 and ISG43, which are coordinately induced in response to biologic and genotoxic stresses. ISG15 and ISG43 encode a ubiquitin-like protein and a ubiquitin-specific protease respectively, which function in the posttranslational regulation of gene expression. These gene products are implicated in stress induced growth suppression. The biological role, regulation by diverse agents, and mechanisms by which these genes function in cells are major interests of the lab.

    An important component of stress response is the posttranscriptional modulation of gene expression. Such regulation provides a mechanism to rapidly change the profile of expressed genes in response to stress stimuli. The 2-5A system is an IFN-regulated RNA decay pathway. RNase-L mediates the cytostatic, antiviral and proapoptotic activities of this pathway. The identificaion of the RNA substrates of RNase-L, and understanding how their regulation relates to RNase-L mediated biological activities constitutes a second focus of research in the lab.

Publications:

Li, X-L., Blackford, J.A., Judge, C.S., Liu, M., Xiao, W., Kalvakolanu, D.V. and Hassel, B.A. (2000) RNase-L-dependent destabilization of interferon-induced mRNAs: a role for the 2-5A system in attenuation of the interferon response. J. Biol. Chem. 275, 8880-8888.

Castelli, J.C., Hassel, B.A., Maran, A., Paranjape, J., Hewitt, J.A., Li, X-L., Hsu, Y-T., Silverman, R.H. and Youle, R.J. (1998). The role of 2’-5’ oligoadenylate-activated ribonuclease in apoptosis. Cell Death and Differentiation 5, 313-320.

Li, X-L., Blackford, J.A. and Hassel, B.A. (1998) RNase-L mediates the antiviral effect of interferon through a selective reduction of viral RNA during encephalomyocarditis virus infection. J. Virol. 72, 2752-2759.

Li, X-L., Boyanapalli, M., Weihua, X., Kalvakolanu, D.V. and Hassel, B.A. (1998) Liposome treatment induces interferon synthesis and activation of interferon-stimulated genes. J. Interferon Cytokine Res. 18, 947-952.

Castelli, J.C., Hassel, B.A., Wood, K.A., Li, X-L., Amemiyz, K., Dalakas, M.C., Torrence, P.F. and Youle, R.J. (1997) A study of the interferon antiviral mechanism: apoptosis activation by the 2-5A system. J. Ex. Med. 186, 1-6.

Squire, J., Zhou, A., Hassel, B.A., Nie, H. and Silverman, R.H. (1994). Localization of the interferon-induced, 2-5A-dependent RNase gene (RNS25A) to human chromosome 1q25. Genomics 19, 174-175.

Dong, B., Xu, L., Zhou, A., Hassel, B.A., Lee, X., Torrence, P.F. and Silverman, R.H. (1994). Intrinsic activities of human 2-5A-dependent RNase produced in insect cells. J. Biol. Chem. 269, 14153-14158.

Zhou, A., Hassel, B.A. and Silverman, R.H. (1993). Expression cloning of 2-5A-dependent RNase: a uniquely regulated mediator of interferon action. Cell 72, 753-765.

Hassel, B.A., Zhou, A., Sotomayor, C. Maran, A. and Silverman, R.H. (1993). A dominant negative mutant of 2-5A-dependent RNase suppresses antiproliferative and antiviral effects of interferon, EMBO J. 12, 3297-3304.

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