Skip to main content

Advertisement

Log in

Immunolocalization of beclin 1, a bcl-2-binding, autophagy-related protein, in the human ovary: possible relation to life span of corpus luteum

  • Regular Article
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

Ovarian tissue homeostasis is maintained by highly regulated cyclic phases of cell proliferation/differentiation and programmed cell death. Compelling evidence indicates that both apoptotic and autophagic types of programmed cell death are involved in the regression of the corpus luteum (CL) in primate species. Beclin 1 is an autophagy-related protein that is involved in the inter-relationships between apoptosis and autophagy, through interaction with the anti-apoptotic protein bcl-2. We studied the presence and expression pattern of beclin 1 in the adult human ovary. In ovarian follicles, beclin 1 immunostaining was found in the theca layer, whereas granulosa cells were negative. After ovulation, beclin 1 immunostaining was present in both theca-lutein and granulosa-lutein areas. The expression of beclin 1 in granulosa-lutein cells was related to the functional and structural status of the CL, being strong at the early and mid luteal phases, barely detectable at the late luteal phase, and absent in granulosa-lutein cells in subsequent cycles. Our results indicated that beclin 1 expression was related to luteal cell survival rather than to cell death. Accordingly, persistent beclin 1 expression was found in granulosa-lutein cells under either physiological (i.e., CL of pregnancy) or pathological (irregularly regressing CL in climacteric women) conditions involving prolonged CL life span. Strong beclin 1 immunostaining was also found in ovarian androgen-producing cells (i.e., secondary interstitial and hilus cells). Our data thus suggest that beclin 1 plays important roles in the regulation of the life span of human CL and ovarian androgen-secreting cells, by maintaining autophagy at levels promoting cell survival rather than cell death.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Abedin MJ, Wang D, McDonnell MA, Lehmann U, Kelekar A (2006) Autophagy delays apoptotic death in breast cancer cells following DNA damage. Cell Death Differ 14:500–510

    Article  CAS  Google Scholar 

  • Bukovsky A, Caudle MR, Keenan JA, Wimalasena J, Upadhyaya NB, Meter SE van (1995) Is corpus luteum regression an immune-mediated event? Localization of immune system components and luteinizing hormone receptor in human corpora lutea. Biol Reprod 53:1373–1384

    Article  PubMed  CAS  Google Scholar 

  • Bukovsky A, Caudle MR, Keenan JA, Wimalasena J, Upadhyaya NB, Meter SE van (1996) Is irregular regression of corpora lutea in climacteric women caused by age-induced alterations in the “tissue control system”? Am J Reprod Immunol 36:327–341

    PubMed  CAS  Google Scholar 

  • Bulling A, Berg FD, Berg U, Duffy DM, Stouffer RL, Ojeda SR, Gratzi M, Mayerhofer A (2000) Identification of an ovarian voltage-activated Na+-channel type: hints to involvement in luteolysis. Mol Endocrinol 14:1064–1074

    Article  PubMed  CAS  Google Scholar 

  • Bursch W, Hochegger K, Török L, Marian B, Ellinger A, Hermann RS (2000) Autophagic and apoptotic types of programmed cell death exhibit different fates of cytoskeletal filaments. J Cell Sci 113:1189–1198

    PubMed  CAS  Google Scholar 

  • Cao L, Leers-Sucheta S, Azhar S (2004) Aging alters the functional expression of enzymatic anti-oxidant defense systems in testicular rat Leydig cells. J Steroid Biochem Mol Biol 88:61–67

    Article  PubMed  CAS  Google Scholar 

  • Chi S, Kitanaka C, Noguchi K, Mochizuki T, Nagashima Y, Shirouzu M, Fujita H, Yoshida M, Chen W, Asai A, Himeno M, Yokoyama S, Kuchino Y (1999) Oncogenic ras triggers cell suicide through the activation of a caspase independent cell death program in human cancer cells. Oncogene 18:2281–2290

    Article  PubMed  CAS  Google Scholar 

  • Dickson SE, Bicknell R, Fraser HM (2001) Mid-luteal angiogenesis and function in the primate is dependent on vascular endothelial growth factor. J Endocrinol 168:409–416

    Article  PubMed  CAS  Google Scholar 

  • Duerrschmidt N, Zabirnyk O, Nowicki M, Ricken M, Hmeidan FA, Blumenauer V, Borlak J, Spanel-Borowski K (2006) LOX-1 receptor mediated autophagy in human granulosa cells as an alternative of programmed cell death. Endocrinology 147:3851–3860

    Article  PubMed  CAS  Google Scholar 

  • Dunn WA Jr (1994) Autophagy and related mechanisms of lysosome-mediated protein degradation. Trends Cell Biol 4:139–143

    Article  PubMed  CAS  Google Scholar 

  • Edinger AL, Thompson CB (2003) Defective autophagy leads to cancer. Cancer Cell 4:422–424

    Article  PubMed  CAS  Google Scholar 

  • Erickson GF, Magoffin DA, Dyer CA, Hofeditz C (1985) The ovarian androgen producing cells: a review of structure/function relationships. Endocr Rev 6:371–399

    PubMed  CAS  Google Scholar 

  • Fraser HM, Lunn SF, Harrison DJ, Kerr JB (1999) Luteal regression in the primate: different forms of cell death during natural and gonadotropin-releasing hormone antagonist or prostaglandin analogue-induced luteolysis. Biol Reprod 61:1468–1479

    Article  PubMed  CAS  Google Scholar 

  • Fukaya T, Funuyama Y, Muakami T, Sugawara J, Yajima A (1997) Does apoptosis contribute follicular atresia and luteal regression in human ovary? Hormone Res 48:20–26

    Article  PubMed  CAS  Google Scholar 

  • Gaytán F, Bellido C, Morales C, Sánchez-Criado JE (1998a) Both prolactin and progesterone in proestrus are necessary for the induction of apoptosis in the regressing corpus luteum in the rat. Biol Reprod 59:1200–1206

    Article  PubMed  Google Scholar 

  • Gaytán F, Morales C, García-Pardo L, Reymundo C, Bellido C, Sánchez-Criado JE (1998b) Macrophages, cell proliferation, and cell death in the human menstrual corpus luteum. Biol Reprod 59:417–425

    Article  PubMed  Google Scholar 

  • Gougeon A (1996) Regulation of ovarian follicular development in primates: facts and hypotheses. Endocr Rev 17:121–155

    Article  PubMed  CAS  Google Scholar 

  • Klionsky DJ, Emr SD (2000) Autophagy as a regulated pathway of cellular degradation. Science 290:1717–1721

    Article  PubMed  CAS  Google Scholar 

  • Levine B, Klionsky DJ (2004) Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 6:463–477

    Article  PubMed  CAS  Google Scholar 

  • Levine B, Yuan J (2005) Autophagy in cell death: an innocent convict? J Clin Invest 115:2679–2688

    Article  PubMed  CAS  Google Scholar 

  • Liang XH, Kleeman LK, Jiang HH, Gordon G, Goldman JE, Berry G, Herman B, Levine B (1998) Protection against fatal Sindbis virus encephalitis by beclin, a novel bcl-2-interacting protein. J Virol 72:8586–8596

    PubMed  CAS  Google Scholar 

  • Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, Levine B (1999) Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402:672–676

    Article  PubMed  CAS  Google Scholar 

  • Lum JJ, Berardinis RJ, Thompson CB (2005) Autophagy in metazoans: cell survival in the land of plenty. Nature Rev Mol Cell Biol 6:439–448

    Article  CAS  Google Scholar 

  • McCracken JA, Custer EE, Lamsa JC (1999) Luteolysis: a neuroendocrine-mediated event. Physiol Rev 79:263–323

    PubMed  CAS  Google Scholar 

  • Morales C, García-Pardo L, Reymundo C, Bellido C, Sánchez-Criado JE, Gaytán F (2000) Different patterns of structural luteolysis in the human corpus luteum of menstruation. Hum Reprod 15:2119–2128

    Article  PubMed  CAS  Google Scholar 

  • Murphy BD (2000) Models of luteinization. Biol Reprod 63:2–11

    Article  PubMed  CAS  Google Scholar 

  • Niswender GD, Nett TM (1988) The corpus luteum and its control. In: Knobil E, Neill JD (eds) The physiology of reproduction. Raven, New York, pp 489–526

    Google Scholar 

  • Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, Packer M, Schneider MD, Levine B (2005) Bcl-2 antiapoptotic proteins inhibit beclin 1-dependent autophagy. Cell 122:927–939

    Article  PubMed  CAS  Google Scholar 

  • Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, Rosen J, Eskelinen EL, Mizushima N, Ohsumi Y, Cattoretti G, Levine B (2003) Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest 112:1809–1820

    Article  PubMed  CAS  Google Scholar 

  • Richards JS (2001) The ovarian follicle—a perspective in 2001. Endocrinology 142:2184–2193

    Article  PubMed  CAS  Google Scholar 

  • Rodger FE, Fraser HM, Duncan WC, Illingworth PJ (1995) Immunolocalization of bcl-2 in the human corpus luteum. Mol Hum Reprod 1:1566–1570

    Article  Google Scholar 

  • Rodger FE, Fraser HM, Krajewski S, Illingworth PJ (1998) Production of the proto-oncogene BAX does not vary with changing in luteal function in women. Mol Hum Reprod 4:27–32

    Article  PubMed  CAS  Google Scholar 

  • Sugino N, Suzuki T, Kashida S, Karube A, Takiguchi S, Kato H (2000) Expression of bcl-2 and bax in the human corpus luteum during the menstrusl cycle and in early pregnancy: regulation by human chorionic gonadotropin. J Clin Endocrinol Metab 85:4379–4386

    Article  PubMed  CAS  Google Scholar 

  • Takacs-Vellai K, Vellai T, Puoti A, Passannante M, Wicky C, Streit A, Kovacs AL, Müller F (2005) Inactivation of the autophagy gene bec-1 triggers apoptotic cell death in C. elegans. Curr Biol 15:1513–1517

    Article  PubMed  CAS  Google Scholar 

  • Terman A, Gustafsson B, Brunk UT (2006) The lysosomal-mitochondrial axis theory of postmitotic aging and cell death. Chem Biol Interact 163:29–37

    Article  PubMed  CAS  Google Scholar 

  • Yi J, Tang XM (1995) Functional implication of autophagy in steroid-secreting cells of the rat. Anat Rec 242:137–146

    Article  PubMed  CAS  Google Scholar 

  • Yue Z, Jin S, Yang C, Levine AJ, Heinz N (2003) Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppresor. Proc Natl Acad Sci USA 100:15077–15082

    Article  PubMed  CAS  Google Scholar 

  • Young FM, Illingworth PJ, Lunn SF, Harrison DJ, Fraser HM (1997) Cell death during luteal regression in the marmoset monkey (Callithrix jacchus). J Reprod Fertil 111:109–119

    Article  PubMed  CAS  Google Scholar 

  • Zeleknik AJ (1998) In vivo responses of the primate corpus luteum to luteinizing hormone and human chorionic gonadotropin. Proc Natl Acad Sci USA 95:11002–11007

    Article  Google Scholar 

Download references

Acknowledgements

The authors are grateful to Pilar Cano and Esteban Tarradas for their technical assistance.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Francisco Gaytán.

Additional information

This study was subsidized by grant BFU 2005-01443 from the DGICYT (Spain).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gaytán, M., Morales, C., Sánchez-Criado, J.E. et al. Immunolocalization of beclin 1, a bcl-2-binding, autophagy-related protein, in the human ovary: possible relation to life span of corpus luteum. Cell Tissue Res 331, 509–517 (2008). https://doi.org/10.1007/s00441-007-0531-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-007-0531-2

Keywords

Navigation