This grant over the past 24 years has supported a wide range of studies focused broadly on immunoglobulin gene expression. This renewal concentrates on the forkhead transcription factor, Foxp1. Conventional Foxp1 knockout (KO) leads to mid-gestation cardiovascular dysfunction and lethality. RAG2-/- reconstitution studies demonstrated an intrinsic block of B cell development at the pro-B stage. Thymic development in Foxp1-/--reconstituted RAG-/- mice is normal, but peripheral CD4 T cell subsets and functions are deregulated. We propose to generation conditional Foxp1 knockout mice to study the effects of intrinsic Foxp1 deficiency on B cell and T cell development. We propose to identify Foxp1 target genes to define pathways and mechanisms by which Foxp1 contributes to normal and malignant B cell development. These studies hold clinical relevance in that Foxp1 over- expression is a hallmark of the most aggressive and worst prognostic subset of diffuse large B cell lymphoma. Philip W. Cancer is often caused by abnormal expression of transcription factors, which regulate the expression of many additional genes. Diffuse large B cell lymphoma (DLBCL) accounts for ~40% of cancers of white blood cells. The transcription factor, Foxp1, is abnormally high in the most aggressive form of DLBCL and has been termed a """"""""signature gene"""""""" of this malignancy. By understanding more about Foxp1 and the genes deregulated by its over-expression, we can better understand basic mechanisms underlying DLBCL. PHS 398/2590

Public Health Relevance

Cancer is often caused by abnormal expression of transcription factors, which regulate the expression of many additional genes. Diffuse large B cell lymphoma (DLBCL) accounts for ~40% of cancers of white blood cells. The transcription factor, Foxp1, is abnormally high in the most aggressive form of DLBCL and has been termed a signature gene of this malignancy. By understanding more about Foxp1 and the genes deregulated by its over-expression, we can better understand basic mechanisms underlying DLBCL.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA031534-28
Application #
8204575
Study Section
Special Emphasis Panel (ZRG1-IMM-B (02))
Program Officer
Mccarthy, Susan A
Project Start
1982-03-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2013-12-31
Support Year
28
Fiscal Year
2012
Total Cost
$249,638
Indirect Cost
$75,977
Name
University of Texas Austin
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78712
Woodworth, Mollie B; Greig, Luciano C; Liu, Kevin X et al. (2016) Ctip1 Regulates the Balance between Specification of Distinct Projection Neuron Subtypes in Deep Cortical Layers. Cell Rep 15:999-1012
Li, Shanru; Morley, Michael; Lu, MinMin et al. (2016) Foxp transcription factors suppress a non-pulmonary gene expression program to permit proper lung development. Dev Biol 416:338-46
Dekker, Joseph D; Park, Daechan; Shaffer 3rd, Arthur L et al. (2016) Subtype-specific addiction of the activated B-cell subset of diffuse large B-cell lymphoma to FOXP1. Proc Natl Acad Sci U S A 113:E577-86
Kim, Peter Geon; Canver, Matthew C; Rhee, Catherine et al. (2016) Interferon-α signaling promotes embryonic HSC maturation. Blood 128:204-16
Brown, Mark A; Foreman, Kenneth; Harriss, June et al. (2015) C-terminal domain of SMYD3 serves as a unique HSP90-regulated motif in oncogenesis. Oncotarget 6:4005-19
Araujo, Daniel J; Anderson, Ashley G; Berto, Stefano et al. (2015) FoxP1 orchestration of ASD-relevant signaling pathways in the striatum. Genes Dev 29:2081-96
Zhao, Jianzhi; Li, Hanjun; Zhou, Rujiang et al. (2015) Foxp1 Regulates the Proliferation of Hair Follicle Stem Cells in Response to Oxidative Stress during Hair Cycling. PLoS One 10:e0131674
Zhao, Haixia; Zhou, Wenrong; Yao, Zhengju et al. (2015) Foxp1/2/4 regulate endochondral ossification as a suppresser complex. Dev Biol 398:242-54
Rasmussen, Tara L; Ma, Yanlin; Park, Chong Yon et al. (2015) Smyd1 facilitates heart development by antagonizing oxidative and ER stress responses. PLoS One 10:e0121765
Wang, Haikun; Geng, Jianlin; Wen, Xiaomin et al. (2014) The transcription factor Foxp1 is a critical negative regulator of the differentiation of follicular helper T cells. Nat Immunol 15:667-75

Showing the most recent 10 out of 48 publications