Normal development of multicellular organisms relies on the balance between cell proliferation, differentiation, and programmed cell death (PCD). Many types of human diseases including cancer appear to be associated with aberrant regulation of PCD and proliferation. Despite the wealth of information, mammalian-signaling pathways for survival and anti-PCD remain poorly understood. We have begun to study cell survival pathways using Akt signaling as a model system. Previous studies of Aki mostly relied on established cell lines. Hence, very little is known about the in vivo function of Akt and signaling pathways that mediate Akt anti-apoptosis activity in primary cells. Our preliminary studies using chimeric mice indicated that Akt plays an important role in hematopoietic cell survival and development. We have also identified several potential in vivo targets of Akt using peptide libraries and genetic screen approaches. The overall objective of this proposal is to understand the architecture of the Akt signaling pathway and the function of Akt in anti-apoptosis signaling and development.
The specific aims of this proposal are to: 1. Investigate the role of Akt in hematopoietic survival using primary cells and in chimera mice. 2. Elucidate the molecular mechanisms of how Akt mediates cell survival.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cell Development and Function Integrated Review Group (CDF)
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Mufson, R Allan
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Baylor College of Medicine
Schools of Medicine
United States
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Liu, Dan; Songyang, Zhou (2009) Genetic mapping of anti-apoptosis pathways in myeloid progenitor cells. Methods Mol Biol 559:283-91
Xu, Jun; Liao, Lan; Qin, Jun et al. (2009) Identification of Flightless-I as a substrate of the cytokine-independent survival kinase CISK. J Biol Chem 284:14377-85
Xin, Huawei; Liu, Dan; Songyang, Zhou (2008) The telosome/shelterin complex and its functions. Genome Biol 9:232
Liu, Dan; Songyang, Zhou (2008) ERM-mediated genetic screens in mammalian cells. Methods Enzymol 446:409-19
Songyang, Zhou; Liu, Dan (2006) Inside the mammalian telomere interactome: regulation and regulatory activities of telomeres. Crit Rev Eukaryot Gene Expr 16:103-18
Xing, Yi; Liu, Dan; Zhang, Rongguang et al. (2004) Structural basis of membrane targeting by the Phox homology domain of cytokine-independent survival kinase (CISK-PX). J Biol Chem 279:30662-9
O'Connor, Matthew S; Safari, Amin; Liu, Dan et al. (2004) The human Rap1 protein complex and modulation of telomere length. J Biol Chem 279:28585-91
Rodriguez, Maria; Li, Shawn S-C; Harper, J Wade et al. (2004) An oriented peptide array library (OPAL) strategy to study protein-protein interactions. J Biol Chem 279:8802-7
Xu, Jun; Liu, Dan; Songyang, Zhou (2002) The role of Asp-462 in regulating Akt activity. J Biol Chem 277:35561-6
Xu, J; Liu, D; Gill, G et al. (2001) Regulation of cytokine-independent survival kinase (CISK) by the Phox homology domain and phosphoinositides. J Cell Biol 154:699-705