The phenotype of cancer cells that present in patients often reflects an immature state and is caused by altered gene expression profiles. I hypothesize that resting, differentiated cells actively maintain specific gene expression profiles and, as such, prevent de-differentiation towards an immature phenotype with altered growth properties. We have previously identified a constitutive signal in resting lymphocytes that dictates gene expression signatures. This signal is generated by an equilibrium between positive and negative regulators, follows a T cell receptor (TCR)-like signaling pathway, and results in basal activity of Erk and Abl kinases. The involvement of Abl kinases may have consequences for CML patients who are receiving STI-571 therapy. In this proposal and in my future line of research, I strive to understand how continuous signal-input in lymphocytes, in vivo, preserves specific gene expression profiles in differentiated cells and, in doing so, prevents unwanted de-differentiation and development of cancer. I propose the following specific aims:
Aims 1, 2: Through the use of innovative mouse models, I will determine the effects of inducible removal of the TCR signaling molecules ZAP-70 and LAT (alone or combined with g-radiation) on constitutive gene expression profiles and maintenance of a differentiated T cell phenotype. Biochemical-, gene expression profiling-, and phenotypical parameters will be determined and correlated.
Aim 3 : To gain a better understanding of controlled gene expression in human peripheral T lymphocytes, and thus its relevance to human disease, I will compare the constitutive signals and gene expression programs in ex vivo T lymphocytes from mice and humans upon pharmacological inhibition, e.g. STI-571, or RNAi targeting of key signaling molecules and link the results to Aims 1, 2.
Aim 4 :I will determine the mechanism of Abl function in T cells by studying its the contribution to constitutive signaling and maintenance of gene expression profiles, which is relevant to CML patients who receive STI-571 (an Abl inhibitor) therapy. These studies will lead to a better understanding of the mechanism of, and the need for, preservation of specific gene expression profiles, thus preventing unwanted de-differentiation and development of T cell malignancies. Resolving these issues will be an important contribution to the understanding of cancer development and may have implications for cancer therapy and prevention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01CA113367-04
Application #
7665061
Study Section
Subcommittee G - Education (NCI)
Program Officer
Lohrey, Nancy
Project Start
2006-08-11
Project End
2011-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
4
Fiscal Year
2009
Total Cost
$149,580
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Limnander, Andre; Zikherman, Julie; Lau, Tannia et al. (2014) Protein kinase C? promotes transitional B cell-negative selection and limits proximal B cell receptor signaling to enforce tolerance. Mol Cell Biol 34:1474-85
Markegard, Evan; Trager, Evan; Yang, Chih-wen Ou et al. (2011) Basal LAT-diacylglycerol-RasGRP1 signals in T cells maintain TCR? gene expression. PLoS One 6:e25540
Chakraborty, Arup K; Das, Jayajit; Zikherman, Julie et al. (2009) Molecular origin and functional consequences of digital signaling and hysteresis during Ras activation in lymphocytes. Sci Signal 2:pt2
Das, Jayajit; Ho, Mary; Zikherman, Julie et al. (2009) Digital signaling and hysteresis characterize ras activation in lymphoid cells. Cell 136:337-51