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. 2001 Oct;85(10):1237–1243. doi: 10.1136/bjo.85.10.1237

Light induced apoptosis is accelerated in transgenic retina overexpressing human EAT/mcl-1, an anti-apoptotic bcl-2 related gene

K Shinoda 1, Y Nakamura 1, K Matsushita 1, K Shimoda 1, H Okita 1, M Fukuma 1, T Yamada 1, H Ohde 1, Y Oguchi 1, J Hata 1, A Umezawa 1
PMCID: PMC1723738  PMID: 11567971

Abstract

BACKGROUND/AIM—EAT/mcl-1 (EAT), an immediate early gene, functions in a similar way to bcl-2 in neutralising Bax mediated cytotoxicity, suggesting that EAT is a blocker of cell death. The aim of this study was to determine the effect of overexpression of the human EAT gene on light induced retinal cell apoptosis.
METHODS—EAT transgenic mice incorporating the EF-1α promoter were utilised, and expression of human EAT was detected by RT-PCR. Light damage was induced by raising mice under constant illumination. Two groups of animals, EAT transgenic mice (n=14) and littermates (n=13), were examined by ERG testing and histopathology at regular time points up to 20 weeks of constant light stimulation. Electrophysiological and histopathological findings were evaluated by established systems of arbitrary scoring as scores 0-2 and scores 0-3, respectively.
RESULTS—The mean score (SD) of ERG response was significantly lower in EAT transgenic mice (0.79 (0.89)) than in littermates (1.69 (0.48)) (p<0.01). Although the differences between the two survival curves did not reach statistical significance (p=0.1156), the estimated incidence of electrophysiological retinal damage was higher in EAT mice (0.0495/mouse/week; 95% confidence interval (CI) 0.0347-0.0500) than in littermates (0. 0199/mouse/week; 95% CI 0.0035-0.0364). The mean scores (SD) for histopathological retinal degeneration were 2.31 (0.63) in littermates and 1.43 (1.22) in EAT transgenic mice (p=0.065). However, Kaplan-Meier curves for histopathological failure in two groups of mice showed that retinal photoreceptor cells were preserved significantly against constant light in the littermate compared with transgenic mice (p=0.0241). The estimated incidence of histopathological retinal damage was 0.0042/mouse/week in the littermates (95% CI 0-0.0120) and 0.0419/mouse/week in the EAT mice (95% CI 0.0286-0.0500).
CONCLUSION—Retinal photoreceptor cell apoptosis under constant light stimulation is likely to be accelerated in transgenic retina overexpressing EAT.



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Figure 1  .

Figure 1  

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Expression of the human EAT transgene. (A) Southern blot analysis of tail DNA from heterozygote transgenic lines. EcoRI digested tail genomic DNA was hybridised with a 32P labelled EF1α-EAT probe. Kilobase size markers are shown on the left. Orientation of the human EAT transgene was determined to be head to tail in all lines. The copy numbers of the transgene per diploid genome for each line are: 150 (E3), and 20 (E12), as shown in lanes 1 and 2, respectively. To determine the copy number of the transgene, transgene fragment copy numbers were also hybridised. (B) Schema of the EF1α human EAT (EF1α-EAT) transgene construct. The PvuI fragment was used as the transgene. The same 6.7 kb PvuI fragment was used as a probe for Southern blot hybridisation. This human EAT transgene, driven by the EF-1α promoter, was injected into the fertilised eggs. (C) Expression of the human EAT transgene as assayed in isolated retinas from the transgenic lines. RT-PCR was performed with a primer set which detected only the human EAT gene without detecting the endogenous murine EAT gene (lane 1: non-transgenic mice; lane 2: E12; lane 3: E13; lane 4: no RNA; lane 5: plasmid containing the human EAT gene). Retinas from a non-transgenic mouse and the human EAT DNA served as negative and positive controls, respectively. A 100 bp ladder is shown as a size marker in lane M. β actin (729 bp) RT-PCR products are shown to demonstrate the integrity of the isolated RNA (lower section).

Figure 2  .

Figure 2  

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Electroretinograms of mice in which light damage was induced by constant light stimulation. (A) The ERG responses were scored by three observers unaware of the EAT genotype for the degree of potential rescue. The scores were based on scale 0 (severe damage with little or no rescue; almost non-recordable), 1 (little damage; a-wave and b-wave seen without oscillatory potentials), and 2 (no damage; a, b-wave amplitude and oscillatory potentials well preserved). Arrows indicate the point of light stimulation. (B) The ERG responses of each mouse. Mice were raised under cyclic room lighting until 35-91 days of age and then were placed in a temperature controlled environmental chamber illuminated continuously by 26 white fluorescent bulbs (40 W). The illumination in the chamber ranged from 400 to 500 lux. (C) Kaplan-Meier survival analysis of electrophysiological responses after constant light stimulation in EAT transgenic mice (solid circle) and littermates (open circle). Criteria for success and failure are described in the Materials and methods section. The estimated incidence of electrophysiological retinal damage was 0.0199/mouse/week in littermates, and 0.0495/mouse/week in EAT transgenic mice.

Figure 3  .

Figure 3  

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Light micrographs of mouse retinas taken from the posterior to equatorial region in the superior hemisphere of the eye. (A) Histological sections cut along the vertical meridian were scored by three observers for the degree of potential rescue, since the region is most sensitive to the damaging effects of constant light. The scores were: score 1 (the outer nuclear layer (ONL) has been reduced to about 3-5 rows of nuclei; disorganised inner segment (IS) and outer segment (OS) are still present), score 2 (photoreceptor IS and some disorganised OS are still present; the ONL still consists of approximately 6-8 rows of nuclei) and score 3 (almost normal structure with 9-10 rows of photoreceptor nuclei comprising the ONL). (B) Kaplan-Meier survival analysis of histopathological findings of the retina after constant light stimulation in the EAT transgenic mice (solid circle) and littermate (open circle). Criteria for success and failure are described in the Materials and methods section. The estimated incidence of histopathological retinal damage was 0.0042/mouse/week in the littermates and 0.0419/mouse/week in the EAT transgenic mice.

Figure 4  .

Figure 4  

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Schematic model of the mechanism of EAT transgene incorporation in promoting light induced apoptosis in the retina. Light triggers a signal cascade mechanism which initiates the apoptotic signal through activation of the JNK (SAPK) pathways and/or c-fos (AP-1) transcriptional pathways. EAT and other Bcl-2 related proteins act at the outer membrane of the mitochondria76 where the heterodimeric balance of bcl-2 related genes regulates the final execution stages of the apoptotic cascade. Bcl-2 related genes regulate mitochondrial membrane function; a loss in mitochondrial transmembrane potential leads to the release of AIF and cytochrome c. These factors then trigger apoptosis in which the caspase activated cascade leads to the activation of endonucleases resulting in DNA fragmentation. We hypothesise that incorporation of the EAT transgene shifts the balance of bcl-2 related heterodimeric molecules in the direction of promoting apoptotic effector signals. EAT promotes light induced apoptosis in retina by the above mechanism.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abler A. S., Chang C. J., Ful J., Tso M. O., Lam T. T. Photic injury triggers apoptosis of photoreceptor cells. Res Commun Mol Pathol Pharmacol. 1996 May;92(2):177–189. [PubMed] [Google Scholar]
  2. Akgul C., Moulding D. A., White M. R., Edwards S. W. In vivo localisation and stability of human Mcl-1 using green fluorescent protein (GFP) fusion proteins. FEBS Lett. 2000 Jul 28;478(1-2):72–76. doi: 10.1016/s0014-5793(00)01809-3. [DOI] [PubMed] [Google Scholar]
  3. Akgul C., Turner P. C., White M. R., Edwards S. W. Functional analysis of the human MCL-1 gene. Cell Mol Life Sci. 2000 Apr;57(4):684–691. doi: 10.1007/PL00000728. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Ando T., Umezawa A., Suzuki A., Okita H., Sano M., Hiraoka Y., Aiso S., Saruta T., Hata J. EAT/mcl-1, a member of the bcl-2 related genes, confers resistance to apoptosis induced by cis-diammine dichloroplatinum (II) via a p53-independent pathway. Jpn J Cancer Res. 1998 Dec;89(12):1326–1333. doi: 10.1111/j.1349-7006.1998.tb00530.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Boise L. H., González-García M., Postema C. E., Ding L., Lindsten T., Turka L. A., Mao X., Nuñez G., Thompson C. B. bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell. 1993 Aug 27;74(4):597–608. doi: 10.1016/0092-8674(93)90508-n. [DOI] [PubMed] [Google Scholar]
  6. Boyd J. M., Gallo G. J., Elangovan B., Houghton A. B., Malstrom S., Avery B. J., Ebb R. G., Subramanian T., Chittenden T., Lutz R. J. Bik, a novel death-inducing protein shares a distinct sequence motif with Bcl-2 family proteins and interacts with viral and cellular survival-promoting proteins. Oncogene. 1995 Nov 2;11(9):1921–1928. [PubMed] [Google Scholar]
  7. Brady H. J., Gil-Gómez G., Kirberg J., Berns A. J. Bax alpha perturbs T cell development and affects cell cycle entry of T cells. EMBO J. 1996 Dec 16;15(24):6991–7001. [PMC free article] [PubMed] [Google Scholar]
  8. Brady H. J., Salomons G. S., Bobeldijk R. C., Berns A. J. T cells from baxalpha transgenic mice show accelerated apoptosis in response to stimuli but do not show restored DNA damage-induced cell death in the absence of p53. EMBO J. 1996 Mar 15;15(6):1221–1230. [PMC free article] [PubMed] [Google Scholar]
  9. Chen E. Inhibition of cytochrome oxidase and blue-light damage in rat retina. Graefes Arch Clin Exp Ophthalmol. 1993 Jul;231(7):416–423. doi: 10.1007/BF00919652. [DOI] [PubMed] [Google Scholar]
  10. Chen J., Flannery J. G., LaVail M. M., Steinberg R. H., Xu J., Simon M. I. bcl-2 overexpression reduces apoptotic photoreceptor cell death in three different retinal degenerations. Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):7042–7047. doi: 10.1073/pnas.93.14.7042. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Cheng E. H., Kirsch D. G., Clem R. J., Ravi R., Kastan M. B., Bedi A., Ueno K., Hardwick J. M. Conversion of Bcl-2 to a Bax-like death effector by caspases. Science. 1997 Dec 12;278(5345):1966–1968. doi: 10.1126/science.278.5345.1966. [DOI] [PubMed] [Google Scholar]
  12. Chittenden T., Harrington E. A., O'Connor R., Flemington C., Lutz R. J., Evan G. I., Guild B. C. Induction of apoptosis by the Bcl-2 homologue Bak. Nature. 1995 Apr 20;374(6524):733–736. doi: 10.1038/374733a0. [DOI] [PubMed] [Google Scholar]
  13. Chou J. J., Li H., Salvesen G. S., Yuan J., Wagner G. Solution structure of BID, an intracellular amplifier of apoptotic signaling. Cell. 1999 Mar 5;96(5):615–624. doi: 10.1016/s0092-8674(00)80572-3. [DOI] [PubMed] [Google Scholar]
  14. Cideciyan A. V., Hood D. C., Huang Y., Banin E., Li Z. Y., Stone E. M., Milam A. H., Jacobson S. G. Disease sequence from mutant rhodopsin allele to rod and cone photoreceptor degeneration in man. Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):7103–7108. doi: 10.1073/pnas.95.12.7103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Clem R. J., Cheng E. H., Karp C. L., Kirsch D. G., Ueno K., Takahashi A., Kastan M. B., Griffin D. E., Earnshaw W. C., Veliuona M. A. Modulation of cell death by Bcl-XL through caspase interaction. Proc Natl Acad Sci U S A. 1998 Jan 20;95(2):554–559. doi: 10.1073/pnas.95.2.554. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Cruickshanks K. J., Klein R., Klein B. E. Sunlight and age-related macular degeneration. The Beaver Dam Eye Study. Arch Ophthalmol. 1993 Apr;111(4):514–518. doi: 10.1001/archopht.1993.01090040106042. [DOI] [PubMed] [Google Scholar]
  17. D'Sa-Eipper C., Subramanian T., Chinnadurai G. bfl-1, a bcl-2 homologue, suppresses p53-induced apoptosis and exhibits potent cooperative transforming activity. Cancer Res. 1996 Sep 1;56(17):3879–3882. [PubMed] [Google Scholar]
  18. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  19. Flannery J. G., Farber D. B., Bird A. C., Bok D. Degenerative changes in a retina affected with autosomal dominant retinitis pigmentosa. Invest Ophthalmol Vis Sci. 1989 Feb;30(2):191–211. [PubMed] [Google Scholar]
  20. Gibson L., Holmgreen S. P., Huang D. C., Bernard O., Copeland N. G., Jenkins N. A., Sutherland G. R., Baker E., Adams J. M., Cory S. bcl-w, a novel member of the bcl-2 family, promotes cell survival. Oncogene. 1996 Aug 15;13(4):665–675. [PubMed] [Google Scholar]
  21. Gross A., McDonnell J. M., Korsmeyer S. J. BCL-2 family members and the mitochondria in apoptosis. Genes Dev. 1999 Aug 1;13(15):1899–1911. doi: 10.1101/gad.13.15.1899. [DOI] [PubMed] [Google Scholar]
  22. Hafezi F., Marti A., Munz K., Remé C. E. Light-induced apoptosis: differential timing in the retina and pigment epithelium. Exp Eye Res. 1997 Jun;64(6):963–970. doi: 10.1006/exer.1997.0288. [DOI] [PubMed] [Google Scholar]
  23. Hanaoka K., Hayasaka M., Uetsuki T., Fujisawa-Sehara A., Nabeshima Y. A stable cellular marker for the analysis of mouse chimeras: the bacterial chloramphenicol acetyltransferase gene driven by the human elongation factor 1 alpha promoter. Differentiation. 1991 Dec;48(3):183–189. doi: 10.1111/j.1432-0436.1991.tb00256.x. [DOI] [PubMed] [Google Scholar]
  24. Hanna N., Peri K. G., Abran D., Hardy P., Doke A., Lachapelle P., Roy M. S., Orquin J., Varma D. R., Chemtob S. Light induces peroxidation in retina by activating prostaglandin G/H synthase. Free Radic Biol Med. 1997;23(6):885–897. doi: 10.1016/s0891-5849(97)00083-x. [DOI] [PubMed] [Google Scholar]
  25. Hao W., Fong H. K. Blue and ultraviolet light-absorbing opsin from the retinal pigment epithelium. Biochemistry. 1996 May 21;35(20):6251–6256. doi: 10.1021/bi952420k. [DOI] [PubMed] [Google Scholar]
  26. Inohara N., Ding L., Chen S., Núez G. harakiri, a novel regulator of cell death, encodes a protein that activates apoptosis and interacts selectively with survival-promoting proteins Bcl-2 and Bcl-X(L). EMBO J. 1997 Apr 1;16(7):1686–1694. doi: 10.1093/emboj/16.7.1686. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Joseph R. M., Li T. Overexpression of Bcl-2 or Bcl-XL transgenes and photoreceptor degeneration. Invest Ophthalmol Vis Sci. 1996 Nov;37(12):2434–2446. [PubMed] [Google Scholar]
  28. Knudson C. M., Tung K. S., Tourtellotte W. G., Brown G. A., Korsmeyer S. J. Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science. 1995 Oct 6;270(5233):96–99. doi: 10.1126/science.270.5233.96. [DOI] [PubMed] [Google Scholar]
  29. Kozopas K. M., Yang T., Buchan H. L., Zhou P., Craig R. W. MCL1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to BCL2. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3516–3520. doi: 10.1073/pnas.90.8.3516. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Krajewski S., Bodrug S., Krajewska M., Shabaik A., Gascoyne R., Berean K., Reed J. C. Immunohistochemical analysis of Mcl-1 protein in human tissues. Differential regulation of Mcl-1 and Bcl-2 protein production suggests a unique role for Mcl-1 in control of programmed cell death in vivo. Am J Pathol. 1995 Jun;146(6):1309–1319. [PMC free article] [PubMed] [Google Scholar]
  31. Kroemer G. The proto-oncogene Bcl-2 and its role in regulating apoptosis. Nat Med. 1997 Jun;3(6):614–620. doi: 10.1038/nm0697-614. [DOI] [PubMed] [Google Scholar]
  32. LaVail M. M., Gorrin G. M., Yasumura D., Matthes M. T. Increased susceptibility to constant light in nr and pcd mice with inherited retinal degenerations. Invest Ophthalmol Vis Sci. 1999 Apr;40(5):1020–1024. [PubMed] [Google Scholar]
  33. Lau L. F., Nathans D. Expression of a set of growth-related immediate early genes in BALB/c 3T3 cells: coordinate regulation with c-fos or c-myc. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1182–1186. doi: 10.1073/pnas.84.5.1182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Li Z. Y., Jacobson S. G., Milam A. H. Autosomal dominant retinitis pigmentosa caused by the threonine-17-methionine rhodopsin mutation: retinal histopathology and immunocytochemistry. Exp Eye Res. 1994 Apr;58(4):397–408. doi: 10.1006/exer.1994.1032. [DOI] [PubMed] [Google Scholar]
  35. Lin E. Y., Orlofsky A., Wang H. G., Reed J. C., Prystowsky M. B. A1, a Bcl-2 family member, prolongs cell survival and permits myeloid differentiation. Blood. 1996 Feb 1;87(3):983–992. [PubMed] [Google Scholar]
  36. Matsushita K., Umezawa A., Iwanaga S., Oda T., Okita H., Kimura K., Shimada M., Tanaka M., Sano M., Ogawa S. The EAT/mcl-1 gene, an inhibitor of apoptosis, is up-regulated in the early stage of acute myocardial infarction. Biochim Biophys Acta. 1999 Nov 16;1472(3):471–478. doi: 10.1016/s0304-4165(99)00149-x. [DOI] [PubMed] [Google Scholar]
  37. McDonnell J. M., Fushman D., Milliman C. L., Korsmeyer S. J., Cowburn D. Solution structure of the proapoptotic molecule BID: a structural basis for apoptotic agonists and antagonists. Cell. 1999 Mar 5;96(5):625–634. doi: 10.1016/s0092-8674(00)80573-5. [DOI] [PubMed] [Google Scholar]
  38. McDonnell T. J., Deane N., Platt F. M., Nunez G., Jaeger U., McKearn J. P., Korsmeyer S. J. bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell. 1989 Apr 7;57(1):79–88. doi: 10.1016/0092-8674(89)90174-8. [DOI] [PubMed] [Google Scholar]
  39. Moulding D. A., Giles R. V., Spiller D. G., White M. R., Tidd D. M., Edwards S. W. Apoptosis is rapidly triggered by antisense depletion of MCL-1 in differentiating U937 cells. Blood. 2000 Sep 1;96(5):1756–1763. [PubMed] [Google Scholar]
  40. Moulding D. A., Quayle J. A., Hart C. A., Edwards S. W. Mcl-1 expression in human neutrophils: regulation by cytokines and correlation with cell survival. Blood. 1998 Oct 1;92(7):2495–2502. [PubMed] [Google Scholar]
  41. Nir I., Kedzierski W., Chen J., Travis G. H. Expression of Bcl-2 protects against photoreceptor degeneration in retinal degeneration slow (rds) mice. J Neurosci. 2000 Mar 15;20(6):2150–2154. doi: 10.1523/JNEUROSCI.20-06-02150.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Okita H., Umezawa A., Suzuki A., Hata J. Up-regulated expression of murine Mcl1/EAT, a bcl-2 related gene, in the early stage of differentiation of murine embryonal carcinoma cells and embryonic stem cells. Biochim Biophys Acta. 1998 Jul 9;1398(3):335–341. doi: 10.1016/s0167-4781(98)00059-1. [DOI] [PubMed] [Google Scholar]
  43. Oltvai Z. N., Milliman C. L., Korsmeyer S. J. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 1993 Aug 27;74(4):609–619. doi: 10.1016/0092-8674(93)90509-o. [DOI] [PubMed] [Google Scholar]
  44. Portera-Cailliau C., Sung C. H., Nathans J., Adler R. Apoptotic photoreceptor cell death in mouse models of retinitis pigmentosa. Proc Natl Acad Sci U S A. 1994 Feb 1;91(3):974–978. doi: 10.1073/pnas.91.3.974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Reed J. C. Balancing cell life and death: bax, apoptosis, and breast cancer. J Clin Invest. 1996 Jun 1;97(11):2403–2404. doi: 10.1172/JCI118684. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Reed J. C. Bcl-2 and the regulation of programmed cell death. J Cell Biol. 1994 Jan;124(1-2):1–6. doi: 10.1083/jcb.124.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Reed J. C. Mechanisms of Bcl-2 family protein function and dysfunction in health and disease. Behring Inst Mitt. 1996 Oct;(97):72–100. [PubMed] [Google Scholar]
  48. Reed J. C., Tsujimoto Y., Alpers J. D., Croce C. M., Nowell P. C. Regulation of bcl-2 proto-oncogene expression during normal human lymphocyte proliferation. Science. 1987 Jun 5;236(4806):1295–1299. doi: 10.1126/science.3495884. [DOI] [PubMed] [Google Scholar]
  49. Remé C. E., Grimm C., Hafezi F., Marti A., Wenzel A. Apoptotic cell death in retinal degenerations. Prog Retin Eye Res. 1998 Oct;17(4):443–464. doi: 10.1016/s1350-9462(98)00009-3. [DOI] [PubMed] [Google Scholar]
  50. Revilla Y., Cebrián A., Baixerás E., Martínez C., Viñuela E., Salas M. L. Inhibition of apoptosis by the African swine fever virus Bcl-2 homologue: role of the BH1 domain. Virology. 1997 Feb 17;228(2):400–404. doi: 10.1006/viro.1996.8395. [DOI] [PubMed] [Google Scholar]
  51. Reynolds J. E., Yang T., Qian L., Jenkinson J. D., Zhou P., Eastman A., Craig R. W. Mcl-1, a member of the Bcl-2 family, delays apoptosis induced by c-Myc overexpression in Chinese hamster ovary cells. Cancer Res. 1994 Dec 15;54(24):6348–6352. [PubMed] [Google Scholar]
  52. Ryder K., Nathans D. Induction of protooncogene c-jun by serum growth factors. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8464–8467. doi: 10.1073/pnas.85.22.8464. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Sano M., Umezawa A., Suzuki A., Shimoda K., Fukuma M., Hata J. Involvement of EAT/mcl-1, an anti-apoptotic bcl-2-related gene, in murine embryogenesis and human development. Exp Cell Res. 2000 Aug 25;259(1):127–139. doi: 10.1006/excr.2000.4977. [DOI] [PubMed] [Google Scholar]
  54. Sato T., Hanada M., Bodrug S., Irie S., Iwama N., Boise L. H., Thompson C. B., Golemis E., Fong L., Wang H. G. Interactions among members of the Bcl-2 protein family analyzed with a yeast two-hybrid system. Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9238–9242. doi: 10.1073/pnas.91.20.9238. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Sedlak T. W., Oltvai Z. N., Yang E., Wang K., Boise L. H., Thompson C. B., Korsmeyer S. J. Multiple Bcl-2 family members demonstrate selective dimerizations with Bax. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7834–7838. doi: 10.1073/pnas.92.17.7834. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Sentman C. L., Shutter J. R., Hockenbery D., Kanagawa O., Korsmeyer S. J. bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes. Cell. 1991 Nov 29;67(5):879–888. doi: 10.1016/0092-8674(91)90361-2. [DOI] [PubMed] [Google Scholar]
  57. Siegel R. M., Katsumata M., Miyashita T., Louie D. C., Greene M. I., Reed J. C. Inhibition of thymocyte apoptosis and negative antigenic selection in bcl-2 transgenic mice. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):7003–7007. doi: 10.1073/pnas.89.15.7003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Simons K. Artificial light and early-life exposure in age-related macular degeneration and in cataractogenic phototoxicity. Arch Ophthalmol. 1993 Mar;111(3):297–298. doi: 10.1001/archopht.1993.01090030015002. [DOI] [PubMed] [Google Scholar]
  59. Strasser A., Harris A. W., Cory S. bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship. Cell. 1991 Nov 29;67(5):889–899. doi: 10.1016/0092-8674(91)90362-3. [DOI] [PubMed] [Google Scholar]
  60. Suzuki A., Umezawa A., Sano M., Nozawa S., Hata J. Involvement of EAT/mcl-1, a bcl-2 related gene, in the apoptotic mechanisms underlying human placental development and maintenance. Placenta. 2000 Mar-Apr;21(2-3):177–183. doi: 10.1053/plac.1999.0458. [DOI] [PubMed] [Google Scholar]
  61. Thompson C. B. Apoptosis in the pathogenesis and treatment of disease. Science. 1995 Mar 10;267(5203):1456–1462. doi: 10.1126/science.7878464. [DOI] [PubMed] [Google Scholar]
  62. Tsang S. H., Chen J., Kjeldbye H., Li W. S., Simon M. I., Gouras P., Goff S. P. Retarding photoreceptor degeneration in Pdegtm1/Pdegtml mice by an apoptosis suppressor gene. Invest Ophthalmol Vis Sci. 1997 Apr;38(5):943–950. [PubMed] [Google Scholar]
  63. Umezawa A., Maruyama T., Inazawa J., Imai S., Takano T., Hata J. Induction of mcl1/EAT, Bcl-2 related gene, by retinoic acid or heat shock in the human embryonal carcinoma cells, NCR-G3. Cell Struct Funct. 1996 Apr;21(2):143–150. doi: 10.1247/csf.21.143. [DOI] [PubMed] [Google Scholar]
  64. Veis D. J., Sorenson C. M., Shutter J. R., Korsmeyer S. J. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell. 1993 Oct 22;75(2):229–240. doi: 10.1016/0092-8674(93)80065-m. [DOI] [PubMed] [Google Scholar]
  65. Wakabayashi K., Saito H., Ebinuma H., Saito Y., Takagi T., Nakamura M., Umezawa A., Hata J., Ishii H. Bcl-2 related proteins are dramatically induced at the early stage of differentiation in human liver cancer cells by a histone deacetylase inhibitor projecting an anti-apoptotic role during this period. Oncol Rep. 2000 Mar-Apr;7(2):285–288. doi: 10.3892/or.7.2.285. [DOI] [PubMed] [Google Scholar]
  66. Williams T. P., Howell W. L. Action spectrum of retinal light-damage in albino rats. Invest Ophthalmol Vis Sci. 1983 Mar;24(3):285–287. [PubMed] [Google Scholar]
  67. Yang E., Korsmeyer S. J. Molecular thanatopsis: a discourse on the BCL2 family and cell death. Blood. 1996 Jul 15;88(2):386–401. [PubMed] [Google Scholar]
  68. Yang E., Zha J., Jockel J., Boise L. H., Thompson C. B., Korsmeyer S. J. Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell. 1995 Jan 27;80(2):285–291. doi: 10.1016/0092-8674(95)90411-5. [DOI] [PubMed] [Google Scholar]
  69. Yang T., Buchan H. L., Townsend K. J., Craig R. W. MCL-1, a member of the BLC-2 family, is induced rapidly in response to signals for cell differentiation or death, but not to signals for cell proliferation. J Cell Physiol. 1996 Mar;166(3):523–536. doi: 10.1002/(SICI)1097-4652(199603)166:3<523::AID-JCP7>3.0.CO;2-R. [DOI] [PubMed] [Google Scholar]
  70. Yang T., Kozopas K. M., Craig R. W. The intracellular distribution and pattern of expression of Mcl-1 overlap with, but are not identical to, those of Bcl-2. J Cell Biol. 1995 Mar;128(6):1173–1184. doi: 10.1083/jcb.128.6.1173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Yin X. M., Oltvai Z. N., Korsmeyer S. J. BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax. Nature. 1994 May 26;369(6478):321–323. doi: 10.1038/369321a0. [DOI] [PubMed] [Google Scholar]
  72. Zhou P., Qian L., Bieszczad C. K., Noelle R., Binder M., Levy N. B., Craig R. W. Mcl-1 in transgenic mice promotes survival in a spectrum of hematopoietic cell types and immortalization in the myeloid lineage. Blood. 1998 Nov 1;92(9):3226–3239. [PubMed] [Google Scholar]

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