Exposure to UV light is a significant environmental and occupational hazard capable of causing acute and chronic inflammatory changes in the cornea. Our long term goal in the corneal epithelium is to characterize the interactions among the cell signaling pathways, which are responsible for UV-induced programmed cell death (apoptosis) and oncogenic changes. We found that an early UV-induced event in these pathways is stimulation of plasma membrane K+ channel activity followed by activation of the stress-induced SEK/JNK signaling pathway, which is a member of the mitogen activated protein kinase (MAPK) superfamily. Interestingly, suppression of UV-induced K+ channel activation completely prevented UV-induced apoptosis through inhibition of UV-induced activation of SEK and JNK kinases. Validation that activation of K+ channel activity is an early event in apoptotic induction is that suppression of K+ channel activity with 4-aminopyridine could not protect corneal epithelial cells from etoposide-induced apoptosis. Thus, we have identified a novel mechanism in which changes in K+ channel activity can modulate SEK/JNK activity and primary rabbit corneal epithelial cell fate. However, nothing is known about other possible interactions linking K+ channel activity to other signaling pathways in the MAPK superfamily as well as other upstream receptors (i.e. EGFR, TNFR1 and CD95/FAS), which are all involved in the control of apoptosis. We hypothesize that activation of EGFR, TNFR1 and CD95/Fas linked signaling pathways in response to UV irradiation is mediated by UV-induced K+ channel hyperactivity.
Three specific aims are proposed to determine: 1) what types of K+ channel are in corneal epithelial cells and how K+ channel activity is modulated by UV irradiation; 2) the effect of altered K+ channel activity on activation of EGFR, TNFR1 and CD95/Fas signaling pathways and UV-responding gene expressions; and 3)whether crosstalk occurs in the apoptotic signaling pathways linked to UV-induced K+ channel activation. Our results will shed new insight into the cell signaling interactions that are involved in linking the apoptotic response to UV irradiation. Furthermore therapeutic measures may be identified which could reduce the incidence of UV-induced apoptotic corneal epithelial damage and increases in corneal epithelial susceptibility to infection and diseases.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY012953-05
Application #
6705055
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Fisher, Richard S
Project Start
2001-02-01
Project End
2006-01-31
Budget Start
2004-02-01
Budget End
2006-01-31
Support Year
5
Fiscal Year
2004
Total Cost
$247,800
Indirect Cost
Name
La Biomed Research Institute/ Harbor UCLA Medical Center
Department
Type
DUNS #
069926962
City
Torrance
State
CA
Country
United States
Zip Code
90502
Wang, Ling; Lu, Luo (2016) Ultraviolet Irradiation-Induced Volume Alteration of Corneal Epithelial Cells. Invest Ophthalmol Vis Sci 57:6747-6756
Wang, Ling; Gao, Jie; Dai, Wei et al. (2008) Activation of Polo-like kinase 3 by hypoxic stresses. J Biol Chem 283:25928-35
Gao, J; Li, T; Lu, L (2007) Functional role of CCCTC binding factor in insulin-stimulated cell proliferation. Cell Prolif 40:795-808
Wang, Ling; Dai, Wei; Lu, Luo (2007) Stress-induced c-Jun activation mediated by Polo-like kinase 3 in corneal epithelial cells. J Biol Chem 282:32121-7
Wang, Ling; Lu, Luo (2007) Pathway-specific effect of caffeine on protection against UV irradiation-induced apoptosis in corneal epithelial cells. Invest Ophthalmol Vis Sci 48:652-60
Li, Tie; Lu, Zhenyu; Lu, Luo (2006) Pax6 regulation in retinal cells by CCCTC binding factor. Invest Ophthalmol Vis Sci 47:5218-26
Lu, Luo (2006) Stress-induced corneal epithelial apoptosis mediated by K+ channel activation. Prog Retin Eye Res 25:515-38
Wu, Dan; Li, Tie; Lu, Zhenyu et al. (2006) Effect of CTCF-binding motif on regulation of PAX6 transcription. Invest Ophthalmol Vis Sci 47:2422-9
Wang, Ling; Reinach, Peter; Lu, Luo (2005) TNF-alpha promotes cell survival through stimulation of K+ channel and NFkappaB activity in corneal epithelial cells. Exp Cell Res 311:39-48
Wang, Ling; Dai, Wei; Lu, Luo (2005) Ultraviolet irradiation-induced K(+) channel activity involving p53 activation in corneal epithelial cells. Oncogene 24:3020-7

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