NCBI Summary:
This gene encodes a protein that regulates autophagy, a catabolic process of degradation induced by starvation. The encoded protein is a component of the phosphatidylinositol-3-kinase (PI3K) complex which mediates vesicle-trafficking processes. This protein is thought to play a role in multiple cellular processes, including tumorigenesis, neurodegeneration and apoptosis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2015]
General function
Cell death/survival, Apoptosis
Comment
Combined apoptosis and autophagy, the process that eliminates the oocytes of atretic follicles in immature rats. Escobar ML et al. We studied the alterations of dying oocytes in 1-28 days old rats using TUNEL method, immunolocalizations of active caspase 3, lamp1, localization of acid phosphatase, and DAPI staining. All procedures were performed in adjacent sections of each oocyte. In most dying oocytes exist simultaneously features of apoptosis as active caspase 3 and DNA breaks, and a large increase of lamp1 and acid phosphatase characteristic of autophagy. Large clumps of compact chromatin and membrane blebbing were absent. Electron microscope observations demonstrated the presence of small clear vesicles and autophagolysosomes. All these features indicate that a large number of oocytes are eliminated by a process sharing features of apoptosis and autophagy. In dying oocytes of new born rats the markers of apoptosis predominate over those of autophagy. However, fragmentation and apoptotic bodies were not found. These features suggest that in different cytophysiological conditions the processes of cell death may be differently modulated.
Cigarette Smoke Exposure Elicits Increased Autophagy and Dysregulation of Mitochondrial Dynamics in Murine Granulosa Cells. Gannon AM et al. Cigarette smoking is a lifestyle behavior associated with significant adverse health effects including subfertility and premature ovarian failure. Cigarette smoke contains a number of chemicals, many of which are involved in the generation of reactive oxygen species, which can lead to apoptosis and autophagy. Autophagy is a fundamental process that removes damaged organelles and proteins through lysosomal degradation. The relevance of autophagy to toxicant-induced changes in ovarian function is largely unexplored. Previously, we reported that exposure to cigarette smoke causes follicle loss, oxidative stress, activation of the autophagy pathway, and a decrease in manganese superoxide dismutase expression (which points to altered mitochondrial function). Therefore, our objective was to test whether cigarette smoke exposure results in the dysregulation of mitochondrial repair mechanisms leading to loss of follicles via autophagy-mediated granulosa cell death. In this study, mice were exposed to cigarette smoke or room air for 8 weeks. The expression of genes and proteins of autophagy and mitochondrial repair factors were measured using quantitative real time PCR and Western blot, immunohistochemistry and ELISA. Increased expression of parkin and decreased expression of the mitofusins suggest that cigarette smoke exposure triggers mitochondrial damage. Moreover, the autophagy cascade proteins, BECN1 and LC3, were up-regulated, while the antagonist BCL2 was down-regulated following treatment. Taken together, our results suggest cigarette smoke exposure induces dysfunction of mitochondrial repair mechanisms, leading to autophagy-mediated follicle death.
Cellular localization
Comment
3-Methyladenine
autophagy inhibitor//////////////////The role of androgen in autophagy of granulosa cells from PCOS. Li X et al. (2020) Hyperandrogenism is one of the most common causes for anovulation in women and increases the risk for metabolic disorder in PCOS patients. Autophagy plays an important role in dysfunction of endocrine and anovulation. However, the relationship between hyperandrogenism and autophagy in human granulosa cells of PCOS patients remains unclear. By collecting granulosa cells from PCOS patients and non-PCOS patients, we found that the abundance of autophagy-related genes ATG5, ATG7, BECN1 mRNA and the ratio of autophagy marker protein light chain 3B II/I (LC3 II/I) were significantly increased whereas the abundance of the autophagy substrate SQSTM1/p62 was decreased in ovarian granulosa cells from PCOS patients. Furthermore, we demonstrated that BECN1 mRNA abundance in human granulosa cells positively correlated with the basal level of serum total testosterone and androgen up-regulated the abundance of BECN1 mRNA and the ratio of LC3II/LC3I in a dose-dependent manner in cultured granulosa cells. These observations indicated that androgen-induced activation of autophagy may play an important role in the development of PCOS and to explore the autophagy mechanisms involved in PCOS yield new insight into the pathophysiology and therapy of the disorder.//////////////////
Ovarian function
Follicle endowment, Steroid metabolism, Luteolysis, Germ cell development
Comment
BECN1, corpus luteum function, and preterm labor. Gawriluk TR et al. (2015)//////////////////
http://www.landesbioscience.com/journals/3/article/5410/
Article Addendum
Cell death in fetal oocytes: Many players for multiple pathways
Massimo De Felici, Anna Maria Lobascio and Francesca Gioia Klinger
We devised a short-term culture system allowing us to define novel characteristics of programmed cell death (PCD) of fetal oocytes and to underscore new aspects of this process. Mouse fetal oocytes cultured in conditions allowing meiotic progression underwent apoptotic degeneration as revealed by TUNEL staining, DNA ladder, Annexin V binding, PARP cleavage and, usually, caspase activation. TEM observations show, however, recurrent atypical apoptotic morphologies characterized by the absence of chromatin margination and nuclear fragmentation; oocytes with autophagic and necrotic features are also observed. Moreover, under the fluorescence microscope a subpopulation of TUNEL+ oocytes appear morphologically healthy and do not show detectable caspase activity. Finally, caspase inhibitors are able to slow down, but not to abolish, oocyte cell death, whereas calpain inhibitor I significantly reduces the number of TUNEL+ oocytes after 4 days of culture, and rapamycin (mTOR inhibitor) increases such numbers both at day 3 and 4. These observations together with results showing expression in cultured oocytes undergoing cell death of apoptosis inducing factor and Beclin 1, two important players of caspase-independent and autophagic cell death, respectively, demonstrate that fetal oocytes posses and are able to activate several players of various forms of cell death. However, causal correlation among different cell death pathways in such oocytes remains to be determined and stimuli causing the activation of these pathways in vitro and in vivo also clarified.
Addendum to: Lobascio AM, Klinger FG, Scaldaferri ML, Farini D, De Felici M. Analysis of programmed cell death in mouse fetal oocytes. Reproduction 2007; 134:241-52.
Expression regulated by
FSH
Comment
Administration of follicle-stimulating hormone induces autophagy via upregulation of HIF-1α in mouse granulosa cells. Zhou J et al. (2017) Recent studies reported the important role of autophagy in follicular development. However, the underlying molecular mechanisms remain elusive. In this study, we investigated the effect of follicle-stimulating hormone (FSH) on mouse granulosa cells (MGCs). Results indicated that autophagy was induced by FSH, which is known to be the dominant hormone regulating follicular development and granulosa cell (GC) proliferation. The activation of mammalian target of rapamycin (mTOR), a master regulator of autophagy, was inhibited during the process of MGC autophagy. Moreover, MHY1485 (an agonist of mTOR) significantly suppressed autophagy signaling by activating mTOR. The expression of hypoxia-inducible factor 1-alpha (HIF-1α) was increased after FSH treatment. Blocking hypoxia-inducible factor 1-alpha attenuated autophagy signaling. In vitro, CoCl2-induced hypoxia enhanced cell autophagy and affected the expression of beclin1 and BCL2/adenovirus E1B interacting protein 3 (Bnip3) in the presence of FSH. Knockdown of beclin1 and Bnip3 suppressed autophagy signaling in MGCs. Furthermore, our in vivo study demonstrated that the FSH-induced increase in weight was significantly reduced after effectively inhibiting autophagy with chloroquine, which was correlated with incomplete mitophagy process through the PINK1-Parkin pathway, delayed cell cycle, and reduced cell proliferation rate. In addition, chloroquine treatment decreased inhibin alpha subunit, but enhanced the expression of 3 beta-hydroxysteroid dehydrogenase. Blocking autophagy resulted in a significantly lower percentage of antral and preovulatory follicles after FSH stimulation. In conclusion, our results indicate that FSH induces autophagy signaling in MGCs via HIF-1α. In addition, our results provide evidence that autophagy induced by FSH is related to follicle development and atresia.//////////////////
Ovarian localization
Oocyte, Theca
Comment
Immunolocalization of beclin 1, a bcl-2-binding, autophagy-related protein, in the human ovary: possible relation to life span of corpus luteum. Gayt?M et al. 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.
Follicle stages
Corpus luteum
Comment
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
3 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment: Autophagy is a cell survival program for female germ cells in the murine ovary. Gawriluk TR 2011 et al.
It is estimated that infertility affects 15-20% of couples and can arise from female or male reproductive defects. Mouse models have ascribed roles to over 100 genes in the maintenance of female fertility. Although previous models have determined roles for apoptosis in male and female fertility, we find that compromised autophagy within the perinatal ovary, through the loss of Becn1 or Atg7, results in the premature loss of female germ cells. Becn1(+/-) ovaries have a 56% reduction of germ cells compared with control ovaries at post-natal day 1, whereas Atg7(-/-) ovaries lack discernable germ cells at this stage. Thus autophagy appears to be a cell survival mechanism to maintain the endowment of female germ cells prior to establishing primordial follicle pools in the ovary.
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Infertility affects an estimated 15% to 20% of couples and can arise from female or male reproductive defects (Hull et al, 1985). Mouse models have ascribed roles to over 100 genes in the maintenance of female fertility (Matzuk and Lamb, 2008). Although previous models have determined roles for apoptosis in male and female fertility, we find that compromised autophagy within the peri-natal ovary, through loss of Becn1 or Atg7, results in the premature loss of female germ cells. Becn1+/- ovaries have a 56% reduction of germ cells compared to control ovaries at post-natal day 1, whereas Atg7-/- ovaries lack discernable germ cells at this stage. Thus autophagy appears to be a cell survival mechanism to maintain the endowment of female germ cells prior to establishing primordial follicle pools in the ovary.
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment: Beclin-1 deficiency in the murine ovary results in the reduction of progesterone production to promote preterm labor. Gawriluk TR 2014 et al.
Autophagy is an important cellular process that serves as a companion pathway to the ubiquitin-proteasome system to degrade long-lived proteins and organelles to maintain cell homeostasis. Although initially characterized in yeast, autophagy is being realized as an important regulator of development and disease in mammals. Beclin1 (Becn1) is a putative tumor suppressor gene that has been shown to undergo a loss of heterozygosity in 40-75% of human breast, ovarian, and prostate cancers. Because Becn1 is a key regulator of autophagy, we sought to investigate its role in female reproduction by using a conditional knockout approach in mice. We find that pregnant females lacking Becn1 in the ovarian granulosa cell population have a defect in progesterone production and a subsequent preterm labor phenotype. Luteal cells in this model exhibit defective autophagy and a failure to accumulate lipid droplets needed for steroidogenesis. Collectively, we show that Becn1 provides essential functions in the ovary that are essential for mammalian reproduction.
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Species: mouse
Mutation name: type: null mutation fertility: fertile Comment: Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice. Fernández ÁF et al. (2018) Autophagy increases the lifespan of model organisms; however, its role in promoting mammalian longevity is less well-established1,2. Here we report lifespan and healthspan extension in a mouse model with increased basal autophagy. To determine the effects of constitutively increased autophagy on mammalian health, we generated targeted mutant mice with a Phe121Ala mutation in beclin 1 (Becn1F121A/F121A) that decreases its interaction with the negative regulator BCL2. We demonstrate that the interaction between beclin 1 and BCL2 is disrupted in several tissues in Becn1 F121A/F121A knock-in mice in association with higher levels of basal autophagic flux. Compared to wild-type littermates, the lifespan of both male and female knock-in mice is significantly increased. The healthspan of the knock-in mice also improves, as phenotypes such as age-related renal and cardiac pathological changes and spontaneous tumorigenesis are diminished. Moreover, mice deficient in the anti-ageing protein klotho 3 have increased beclin 1 and BCL2 interaction and decreased autophagy. These phenotypes, along with premature lethality and infertility, are rescued by the beclin 1(F121A) mutation. Together, our data demonstrate that disruption of the beclin 1-BCL2 complex is an effective mechanism to increase autophagy, prevent premature ageing, improve healthspan and promote longevity in mammals./////////////////Activation of autophagy in early neonatal mice increases primordial follicle number and improves lifelong fertility. Watanabe R et al. (2019) The number of stockpiled primordial follicles are thought to be responsible for the fate of female fertility and reproductive lifetime. We previously reported that starvation in non-suckling early neonatal mice increases the number of primordial follicles with concomitant autophagy activation, suggesting that autophagy may accelerate the formation of primordial follicles. In this study, we attempted to upregulate the numbers of primordial follicles by administering an autophagy inducer and evaluated the progress of primordial follicle formation and their fertility during the life of the mice. To induce autophagy, mice were intraperitoneally injected with the Tat-beclin1 D-11 peptide (0.02 mg/g body weight) at 6-54 h or 60-84 h after birth. In animals that received Tat-beclin 1 D-11 by 54 h after birth, the primordial follicle numbers were significantly increased compared with the control group at 60 h. The ratio of expressed LC3-II/LC3-I proteins was also significantly greater. The numbers of littermates from pregnant females that had been treated with Tat-beclin 1 D-11 were maintained at remarkably greater levels until 10 months old. These results were supported by an abundance of primordial follicles at even 13 to 15 months old. These findings indicate that an enhancement in autophagy in neonatal mice during the follicle formation period accelerates follicle assembly by promoting oocyte survival. Consequently, the stockpile of primordial follicles expands, leading to an improvement in individual lifelong fertility.//////////////////