The laboratory is principally involved in the study of receptor signal transduction for several growth factors and the identification of receptors that share subunits or are members of the same receptor superfamily. These growth factors primarily have effects on cells of lymphoid and hematological origin or as in the case of prolactin, breast tissue normal and transformed. The laboratory has extended its investigations into the role of the JAK/Stat pathway for specific cytokine receptors. Through critical analysis of the IL2, IL4, and prolactin receptor systems we have identified structural and functional requirements responsible for recruitment and activation of JAK and Stat proteins. Additionally, we have identified the structural requirements for the activation of collateral signal pathways associated with PI3 kinase activation and a unique serine kinase which is involved in Stat 5 phosphorylation. The laboratory has continued structure function studies through mutational analysis of JAK2 in order to determine the chemical basis of activation or repression. We have shown that JAK family enzymes are negatively regulated by nitric oxide (NO) a potent physiological mediator produced by monocytes. JAK2 and JAK3 are catalytically inhibited by DE-NO- as well as interleukin induced proliferative responses. These results have suggested a mechanism by which NO participates in immunosuppression. We have identified a trans- inhibitory site within the structure of JAK2 located approximately within the JH4, regian of the enzyme. Mechanistic studies are underway in order to molecularly characterize the phenomenon. AIDS TITLE: N/A LMI

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010253-02
Application #
6161143
Study Section
Special Emphasis Panel (LMI)
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Crea, Francesco; Duhagon Serrat, Maria A; Hurt, Elaine M et al. (2011) BMI1 silencing enhances docetaxel activity and impairs antioxidant response in prostate cancer. Int J Cancer 128:1946-54
Qin, Haiyan R; Kim, Han-Jong; Kim, Joon-Young et al. (2008) Activation of signal transducer and activator of transcription 3 through a phosphomimetic serine 727 promotes prostate tumorigenesis independent of tyrosine 705 phosphorylation. Cancer Res 68:7736-41
Sharifi, Nima; Hurt, Elaine M; Farrar, William L (2008) Androgen receptor expression in prostate cancer stem cells: is there a conundrum? Cancer Chemother Pharmacol 62:921-3
Sharifi, Nima; Farrar, William L (2008) Re: ""Body size, weight cycling, and risk of renal cell carcinoma among postmenopausal women: the women's health initiative (United States)"". Am J Epidemiol 167:1016;author reply 1016
Sharifi, Nima; Hurt, Elaine M; Kawasaki, Brian T et al. (2007) TGFBR3 loss and consequences in prostate cancer. Prostate 67:301-11
Sharifi, Nima; Hamel, Ernest; Lill, Markus A et al. (2007) A bifunctional colchicinoid that binds to the androgen receptor. Mol Cancer Ther 6:2328-36
Hurt, Elaine M; Thomas, Suneetha B; Peng, Benjamin et al. (2006) Reversal of p53 epigenetic silencing in multiple myeloma permits apoptosis by a p53 activator. Cancer Biol Ther 5:1154-60
Wang, Li Hua; Yang, Xiao Yi; Zhang, Xiaohu et al. (2005) Nuclear receptors as negative modulators of STAT3 in multiple myeloma. Cell Cycle 4:242-5
Peng, Benjamin; Hodge, David R; Thomas, Suneetha Betsy et al. (2005) Epigenetic silencing of the human nucleotide excision repair gene, hHR23B, in interleukin-6-responsive multiple myeloma KAS-6/1 cells. J Biol Chem 280:4182-7
Hodge, David R; Peng, Benjamin; Cherry, James C et al. (2005) Interleukin 6 supports the maintenance of p53 tumor suppressor gene promoter methylation. Cancer Res 65:4673-82

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