CREB1/ATF1 activation in photoreceptor degeneration and protection.
OBJECTIVE
The cAMP response element binding protein 1 (CREB1) and activating transcription factor 1 (ATF1) are closely related members of the bZIP superfamily of transcription factors. Both are activated in response to a wide array of stimuli, including cellular stress. This study was conducted to assess the CREB1/ATF1 pathway in photoreceptor disease and protection.


METHODS
The expression levels of p-CREB1, CREB1, and ATF1 were examined by immunoblot and immunohistochemistry in normal canine retina and retinas of several canine models of retinal degeneration (rcd1, rcd2, erd, prcd, XLPRA1, XLPRA2, T4R RHO). Humans retinas affected with age-related macular degeneration (AMD) were also examined. p-CREB1/ATF1 immunolabeling was assessed in normal and rcd1 dogs treated with ciliary neurotrophic factor (CNTF), to examine the effect of a neuroprotective stimulus on activation of CREB1/ATF1.


RESULTS
Native CREB1 and ATF1 as well as phosphorylated CREB1/ATF1 was examined in normal canine retina by immunoblot. The p-CREB1 antibody identified phosphorylated CREB1 and ATF1 and labeled the inner retina only in normal dogs. In degenerate canine and human retinas, strong immunolabeling appeared in rod and cone photoreceptors, indicating increased expression of native CREB1 and ATF1, as well as increased phosphorylation of these proteins. Retinal protection by CNTF in rcd1 dogs was accompanied by a significant increase in the number of p-CREB1/ATF1-labeled photoreceptor nuclei.


CONCLUSIONS
Positive association of CREB1/ATF1 phosphorylation with photoreceptor protection suggests that it may contribute to an innate protective response. These data identify a signaling mechanism in rods and cones of potential importance for therapies of RP and AMD.
Beltran
William A
WA
Section of Ophthalmology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Allore
Heather G
HG
Johnson
Elizabeth
E
Towle
Virginia
V
Tao
Weng
W
Acland
Gregory M
GM
Aguirre
Gustavo D
GD
Zeiss
Caroline J
CJ
D051697:Activating Transcription Factor 1 / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D019393:Arrestin / Q000378:metabolism; D002452:Cell Count; D020934:Ciliary Neurotrophic Factor / Q000627:therapeutic use; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004283:Dog Diseases / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D004285:Dogs; D005260:Female; D005838:Genotype; D006801:Humans; D015151:Immunoblotting / Q000662:veterinary; D007124:Immunoenzyme Techniques / Q000662:veterinary; D008268:Macular Degeneration / Q000378:metabolism* / Q000473:pathology; D008297:Male; D010766:Phosphorylation; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control* / Q000662:veterinary*; D012243:Rhodopsin / Q000378:metabolism
C531110:ATF1 protein, human; D051697:Activating Transcription Factor 1; D019393:Arrestin; C115163:CREB1 protein, human; D020934:Ciliary Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D012243:Rhodopsin