Growth, differentiation, and development of an organism is tightly controlled by the spatial and temporal regulation of transcription factors. NF-kappaB proteins are a large family of transcription factors which control the expression of a vast array of genes involved in immune response, cancer, viral infections, programmed cell death, developmental clues, etc. Unlike most transcription factors, NF-kappaB proteins are sequestered in the cytoplasm in association with inhibitory proteins (IkappaBs). In response to an external signal, the IkappaB proteins are phosphorylated, ubiquitinated, and degraded by proteosomes to allow the release of the NF-kappaB protein to the nucleus where they can bind to the cognate DNA binding sites and activate transcription of specific genes. The seminal event in the activation of NF-kappaB proteins in response to exogenous stimulus is the degradation of IkappaB proteins. In this proposal we are planning to study the components of a large cytoplasmic complex, referred to as IKK, which receives the signal and modulates the degradation of IkappaB protein. We plan to understand the molecular function of the two kinases, IKK1 and IKK2 present in the IKK complex because they phosphorylate IkappaBalpha at unique residues to trigger its degradation process. We have generated mice where the two kinases have been genetically deleted either singly or both of them. The remarkable but quite distinct influences of these kinases on mice development lead us to ask if these kinases have distinctly different roles in growth and development. We plan to study the nature and mechanism of brain malformation in double """"""""knockout"""""""" mice (both IKK1 and IKK2 are removed). We will also study what specific signal pathways each of these kinases respond to in different tissues. By using novel DNA microarray technology (thousands of genes can be analyzed simultaneously) we will identify novel genes induced by NF-kappaB proteins in cell growth and programmed cell death (apoptosis). We also plan to determine if the two kinases are involved in functions other that induced phosphorylation of IkappaB proteins. Finally, we also propose to generate viral vectors containing mutant forms of IKKs or IkappaB proteins and study their effect on experimental model systems like asthma, rheumatoid arthritis, cancer models (radiation damage, chemotoxic agents), and development. We believe that the experiments proposed here will allow us to decipher the molecular mechanism of regulation of NF-kappaB proteins. The detailed knowledge of this important signal pathway will allow us to develop strategies for curing diseases ranging from inflammation to cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI048034-03
Application #
6534281
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Mallia, Conrad M
Project Start
2000-09-30
Project End
2005-05-31
Budget Start
2002-09-01
Budget End
2003-05-31
Support Year
3
Fiscal Year
2002
Total Cost
$572,152
Indirect Cost
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
005436803
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Polley, Smarajit; Passos, Dario Oliveira; Huang, De-Bin et al. (2016) Structural Basis for the Activation of IKK1/?. Cell Rep 17:1907-1914
Wickersham, Ian R; Sullivan, Heather A; Pao, Gerald M et al. (2015) Lentiviral vectors for retrograde delivery of recombinases and transactivators. Cold Spring Harb Protoc 2015:368-74
Menon, Tushar; Firth, Amy L; Scripture-Adams, Deirdre D et al. (2015) Lymphoid regeneration from gene-corrected SCID-X1 subject-derived iPSCs. Cell Stem Cell 16:367-72
Font-Burgada, Joan; Shalapour, Shabnam; Ramaswamy, Suvasini et al. (2015) Hybrid Periportal Hepatocytes Regenerate the Injured Liver without Giving Rise to Cancer. Cell 162:766-79
Yeddula, Narayana; Xia, Yifeng; Ke, Eugene et al. (2015) Screening for tumor suppressors: Loss of ephrin receptor A2 cooperates with oncogenic KRas in promoting lung adenocarcinoma. Proc Natl Acad Sci U S A 112:E6476-85
Firth, Amy L; Menon, Tushar; Parker, Gregory S et al. (2015) Functional Gene Correction for Cystic Fibrosis in Lung Epithelial Cells Generated from Patient iPSCs. Cell Rep 12:1385-90
Narasimamurthy, Rajesh; Hatori, Megumi; Nayak, Surendra K et al. (2012) Circadian clock protein cryptochrome regulates the expression of proinflammatory cytokines. Proc Natl Acad Sci U S A 109:12662-7
Liu, Fei; Xia, Yifeng; Parker, Aaron S et al. (2012) IKK biology. Immunol Rev 246:239-53
Xia, Yifeng; Yeddula, Narayana; Leblanc, Mathias et al. (2012) Reduced cell proliferation by IKK2 depletion in a mouse lung-cancer model. Nat Cell Biol 14:257-65
Murphy, Samantha H; Suzuki, Kotaro; Downes, Michael et al. (2011) Tumor suppressor protein (p)53, is a regulator of NF-kappaB repression by the glucocorticoid receptor. Proc Natl Acad Sci U S A 108:17117-22

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