Ionizing radiation (IR) is an essential therapeutic modality for cancer, leukemia and lymphoma, but its usefulness is limited by its toxicity to normal tissue. Lymphoid and hematopoietic tissues exhibit a high degree of IR sensitivity and, therefore, typically determine the limits of IR therapy. Although DNA damage induced by IR is one of the main causes of tissue toxicity, an increasing body of evidence demonstrates that the expression of certain gene products via IR-induced activation of specific transcription factors also significantly contributes to this toxicity. Activation of particular transcription factors and the subsequent induction of specific gene products in lymphoid tissues and bone marrow (BM) may be responsible for their high radiosensitivity. We have recently demonstrated that IR induces lymphocyte-specific activation of NF-kappaB in vivo via a unique signal transduction pathway that is independent of IkappaB degradation but involves the production of reactive oxygen species (ROS) and protein tyrosine phosphorylation by protein tyrosine kinase(s) (PTK). It has been shown that activation of NF-kappaB by T cell receptor stimulation and genotoxic stress induces T cell expression of FasL which in turn, leads to apoptotic cell death. We hypothesize that a major component of IR-induced toxicity in lymphoid tissues and BM is mediated through the specific activation of NF-kappaB in lymphocytes via a lymphocyte-specific signal transduction pathway. This leads to the up-regulation of FasL expression and subsequent Fas-FasL interaction which causes undesirable lymphocyte apoptosis and bystander killing of hematopoietic stem cells (HSC) in the absence of IR-induced lethal DNA damage. To test this hypothesis, we will pursue the following Specific Aims: (a) to determine whether IR activates NF-kappaB in lymphocytes via tyrosine phosphorylation of IkappaBalpha by a lymphocyte-specific non-transmembrane PTK pathway; (b) to identify the cellular origin of IR-induced Fas and FasL expression in the spleen and BM and determine if Fas-FasL interaction plays a significant role in IR-induced lymphocyte and HSC apoptosis and (c) to examine whether activation of NF-kappaB mediates IR-induced T cell expression of FasL and determine if inhibition of NF-kappaB activation provides immune and hematopoietic protection via down- regulation of Fas-FasL interaction. These studies will provide new insights into the molecular mechanisms underlying the susceptibility of lymphoid and hematopoietic tissues to IR-induced tissue damage and offer novel strategies to improve tumor radiotherapy by reducing radiation toxicity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA086860-01
Application #
6158875
Study Section
Radiation Study Section (RAD)
Program Officer
Stone, Helen B
Project Start
2000-09-01
Project End
2000-10-31
Budget Start
2000-09-01
Budget End
2000-10-31
Support Year
1
Fiscal Year
2000
Total Cost
$7,755
Indirect Cost
Name
University of Kentucky
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
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Shao, Lijian; Feng, Wei; Lee, Kyung-Jong et al. (2012) A sensitive and quantitative polymerase chain reaction-based cell free in vitro non-homologous end joining assay for hematopoietic stem cells. PLoS One 7:e33499
Diaz-Montero, C Marcela; Wang, Yong; Shao, Lijian et al. (2012) The glutathione disulfide mimetic NOV-002 inhibits cyclophosphamide-induced hematopoietic and immune suppression by reducing oxidative stress. Free Radic Biol Med 52:1560-8
Berbee, Maaike; Fu, Qiang; Boerma, Marjan et al. (2011) Reduction of radiation-induced vascular nitrosative stress by the vitamin E analog ?-tocotrienol: evidence of a role for tetrahydrobiopterin. Int J Radiat Oncol Biol Phys 79:884-91
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Wang, Yong; Liu, Lingbo; Zhou, Daohong (2011) Inhibition of p38 MAPK attenuates ionizing radiation-induced hematopoietic cell senescence and residual bone marrow injury. Radiat Res 176:743-52
Wang, Yong; Kellner, Joshua; Liu, Lingbo et al. (2011) Inhibition of p38 mitogen-activated protein kinase promotes ex vivo hematopoietic stem cell expansion. Stem Cells Dev 20:1143-52
Shao, Lijian; Li, Hongliang; Pazhanisamy, Senthil K et al. (2011) Reactive oxygen species and hematopoietic stem cell senescence. Int J Hematol 94:24-32
Wu, Lixian; Shao, Lijian; An, Ningfei et al. (2011) IKK? regulates the repair of DNA double-strand breaks induced by ionizing radiation in MCF-7 breast cancer cells. PLoS One 6:e18447

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