Andrea Doseff

Focus

cell death during the innate immune response and oncogenic transformation

Research interests

My laboratory investigates the mechanisms involved in cell death during the innate immune response and oncogenic transformation. We combine molecular, biochemical, cellular biology and bioinformatics approaches to understand the regulation of the apoptotic pathways.

Our studies are focused on the signaling pathways that contribute to the activation and deactivation of caspases, essentials proteases required for apoptosis. The main purpose of our research is that by understanding the mechanisms that regulate the caspases we will be able to manipulate cell death of unwanted cells as a treatment for cancer, inflammation and formation of the atherosclerotic plaque.

One major project in my lab is to identify the proteins that regulate the activation and activity of the inflammatory and killing caspases during monocyte-macrophage-dendritic cell differentiation. This includes the isolation of regulatory proteins and the dissection of the signaling pathways that modulate apoptosis.

We showed that some PKC isoforms act as pro-apoptotic factors phosphorylating caspase-3 and promoting its activity. These pathways may change during differentiation thus allowing the cells to regulate their apoptotic commitment differently depending on their differentiation’s stage.

We have demonstrated a differential role of inflammatory and anti-inflammatory cytokines in the control of the apoptotic machinery of leukocytes.

Furthermore, plant flavonoids are being investigated due to their potential to induce apoptosis in cancer cells and decrease inflammation. These findings may provide a new approach
to regulate the number of unwanted cells during inflammation.

In this context, one of our main interests is to understand the role of kinases, phosphatases and reactive oxygen species in the regulation of caspases and the contribution of the mitochondria during activation and monocyte apoptosis. These results should contribute to a better understanding of basic mechanisms during sepsis, cancer and the formation of the atherosclerotic plaque.

A second area of research involves the characterization of signals produced by dying cells to recruit and promote the clearance of apoptotic bodies by phagocytic cells like the macrophages. We are using biochemical and a proteomic approaches to characterize a compounds produced by dying cells that are chemotactic for macrophages. In addition, using a bioinformatics approach and with the availability of the human proteome, we are trying to characterize new substrates of caspases. These ‘in-silico experiments’ should allow us to identify additional targets of caspases that once validated molecularly can be used to mark unwanted cells for removal by phagocytic cells.

Publications

• Vargo, M.A., Voss, O.H., Cardounel, A.J., Grotewold, E., and Doseff, A.I. (2006). Apigenin-induced-apoptosis is mediated by the activation of PKCdelta and caspases in leukemia cells. Biochem. Pharmacol. [Abstract]
• Voss, O.H., Kim, S., Wewers, M.D. and Doseff, A.I. (2005). Caspase-3 is a phosphoprotein and associates with PKCdelta during spontaneous monocyte apoptosis. J. Biol. Chem. 280: 17371-17379.[Abstract]
• Bao, S., Wang, Y., Sweeney, P., Chaudhuri, A., Doseff, A.I., Marsh, C.B., and Knoell, D.L. (2005). Keratynocyte growth factor induces Akt kinase activity and inhibits Fas-mediated apoptosis in A549 lung epithelial cells. A.J.P. Lung Cell. Mol. Physiol . 288 (1): L36-42.[Abstract]
• Wei G, Guo, J, Doseff, AI, Kusewitt, DF, Man, AK, Oshima, RG, and Ostrowski, MC. (2004). Activated Ets2 is required for persistent inflammatory responses in the motheaten viable model. J. Immunol. 173:1374-1379. [Abstract]
• Elssner, A., Doseff, A.I., Duncan, M., Kotur, M., and Wewers, M.D. (2004). Interleukin-16 is constitutively present in peripheral blood monocytes and spontaneoulsy released during apoptosis. J. Immunol. 172: 7721-7725.
• Doseff, A.I., Baker Jr., J.H., Bourgeois, T.A., and Wewers, M.D. (2003). IL-4-induced apoptosis entails caspase activation and dephosphorylation of ERK. Am. J. Resp. Cell and Mol. Biol. 29: 367-374.[Abstract]
• Rovin, B.H., Wilmer, W.A., Lu, L., Doseff, A.I., Dixon, C., Kotur, M., and Hilbelink, T. (2002). The cyclopentenone prostaglandin 15-deoxy- D 12,14 -prostaglandin J 2 regulates mesangial cell proliferation and death. Kidney Intern. 61: 1293-302. [Abstract]
• Coulter, K.R., Sweeney, P., Doseff, A.I., Wang, Y., Marsh, C.B, Wewers, M.D., Knoell, D.L. (2002). Opposing effect by cytokines on Fas-mediated apoptosis in A549 lung epithelial cells. Am. J. Resp. Cell and Mol. Biol.26: 58-66.
• Goyal, A., Wang, Y., Graham, M.M., Doseff, A.I., Bhatt, N.Y., and Marsh, C.B. (2002). Monocyte survival factors induce Akt activation and suppress caspase-3. Am. J. Resp. Cell and Mol. Biol.26: 224-230. [Abstract]
• Fahy, R.J.*, Doseff, A.I.*, and Wewers, M.D. (1999). Spontaneous human monocyte apoptosis utilizes a caspase-3 dependent pathway which is blocked by endotoxin and is independent of caspase-1. J. Immunol. 163: 1755-1762.
• Kirsch, D.G., Doseff, A.I., Chau, B.N., Lim, D., Souza-Pinto, N.C., Hansford, R., Kastan, M.B., Lazebnik, Y.A., and Hardwick, J.M. (1999). Caspase-3-dependent cleavage of Bcl-2 promotes release of cytochrome c. J. Biol. Chem. 274: 21155-21161. [Abstract]
• Kelley, T.W., Graham, M.M., Doseff, A.I., Pommerantz, R.W., Lau, S.M., Ostrowski, M.C., Franke, T.M., and Marsh, C. B. (1999). Macrophage colony-stimulating factor promotes cell survival through Akt/protein kinase B. J. Biol. Chem. 274: 26393-26398. [Abstract]
• Nestler. H.P., and Doseff, A.I. (1997). A two dimensional, diagonal SDS-PAGE technique to screen for proteases substrates in protein mixtures. Anal. Biochem.251: 122-124.
• Doseff, A.I. , and Arndt, K.T. (1995). Las1 is an essential nuclear protein involved in morphogenesis and cell surface growth. Genetics141: 857-871.
• Doseff, A.I. , Martienssen, R., and Sundaresan, V. (1991). Somatic excision of the Mu1 transposable element of maize. Nucl. Acids Res.19:579-584. [Abstract]
• Barneix, A.J., Doseff, A.I. and Rodgers, C.O. (1989). Nitrate reductase activity in Argentine wheat cultivars. Cereal Research Comm.16: 269-272.