BCL2-associated X protein OKDB#: 905
 Symbols: BAX Species: human
 Synonyms: BCL2L4,Bcl-2 Associated X gene,  Locus: 19q13.3-q13.4 in Homo sapiens


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General Comment The original identification of the gene was reported in 1993 (Oltvai et al., 1993 ). Bax was identified based on its ability to co-immunoprecipitate (heterodimerize) with the anti-apoptotic protein Bcl-2. BAX is a proapoptotic protein with extensive amino acid homology with Bcl-2. Bax forms homodimers and heterodimers with Bcl-2 in vivo. When BAX predominates, programmed cell death is accelerated, and the death repressor activity of Bcl2 is countered (Oltvai et al., 1993).

NCBI Summary: The protein encoded by this gene belongs to the BCL2 protein family. BCL2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein forms a heterodimer with BCL2, and functions as an apoptotic activator. This protein is reported to interact with, and increase the opening of, the mitochondrial voltage-dependent anion channel (VDAC), which leads to the loss in membrane potential and the release of cytochrome c. The expression of this gene is regulated by the tumor suppressor P53 and has been shown to be involved in P53-mediated apoptosis. Multiple alternatively spliced transcript variants, which encode different isoforms, have been reported for this gene. [provided by RefSeq, Jul 2008]
General function Cell death/survival, Apoptosis
Comment
Cellular localization Cytoplasmic, Mitochondrial
Comment Upon receipt by the cell of an apoptotic stimulus, Bax is believed to form homodimers, translocate from the cytoplasm to the mitochondrial membranes, and initiate cytochrome c release leading to caspase activation via a molecular bridge protein termed Apaf-1 (Wolter et al., 1997 and Gross et al., 1998 ).
Ovarian function Follicle endowment, Follicle atresia, Luteolysis, Germ cell development, Oocyte apoptosis
Comment Effect of RNA Interference of BID and BAX mRNAs on Apoptosis in Granulosa Cell-derived KGN Cells. Sai T et al. In mitochondrion-dependent type II apoptosis, BH3-interacting domain death agonist (BID) and BCL-2-associated X protein (BAX) promote death ligand and receptor-mediated cell death. In porcine ovaries, the levels of BID and BAX increase in follicular granulosa cells during atresia. In the present study, to confirm the pro-apoptotic activity of BID and BAX in granulosa cells, we examined the effect of RNA interference of BID or BAX on apoptosis using a human ovarian granulosa tumor cell line, KGN. By reverse transcription polymerase chain reaction (RT-PCR) and Western blotting, expression of BID and BAX was detected in KGN cells. Then, we suppressed BID and BAX mRNA expression in KGN cells using small interfering RNA (siRNA). When BID or BAX was suppressed, a significant decrease in the apoptotic cell rate was noted. In granulosa-derived cells, BID and BAX showed pro-apoptotic activity. These results suggest that BID and BAX act as signal-transducing factors in mitochondrion-dependent type II apoptosis. Many papers have been published on the prominent role of Bax in apoptosis of multiple ovarian cell lineages under both normal and pathological situations. For details, see Tilly et al., 1995 , Knudson et al., 1995 , Springer et al., 1996 , Rueda et al., 1997 , Perez et al., 1997 , Kugu et al., 1998 , Goodman et al., 1998 , Jurisicova et al., 1998 , Perez et al., 1999 , De Felici et al., 1999 and Dharmarajan et al., 1999 . Stallock J, et al reported the pro-apoptotic gene Bax is required for the death of ectopic primordial germ cells during their migration in the mouse embryo. BAX is involved in regulating follicular growth, but is dispensable for follicle atresia in adult mouse ovaries. Greenfeld CR et al. Mammalian females are endowed with a finite number of primordial follicles at birth or shortly thereafter. Immediately following the formation of the primordial follicle pool, cohorts of these follicles are recruited to begin growth, and this recruitment continues until the primordial follicle population is depleted. Once recruited, a follicle will either grow and ovulate or undergo atresia. Follicle atresia results from the apoptotic death of follicular cells. Members of the BCL-2 family of proteins are important regulators of apoptosis in most cells including in the ovary. Here, we tested the hypothesis that the proapoptotic BAX is an important regulator of follicle survival. We used a variety of histological and biochemical techniques to investigate the impact of Bax deletion on follicle growth and death. We observed that the Bax deletion results in delayed vaginal opening and altered follicular growth. Young adult Bax-deficient ovaries contained increased numbers of primordial follicles and a trend towards reduced numbers of growing follicles. Bax deficiency led to a reduction in average litter size, and also a reduction in the number of oocytes ovulated in response to exogenous gonadotropins. In contrast, Bax deficiency did not alter follicle atresia. In conclusion, BAX appears to be an important regulator of follicle growth, but is dispensable for follicle atresia in mice.
Expression regulated by FSH, LH, Growth Factors/ cytokines
Comment Expression of the bax gene in ovarian germ cells (De Felici et al., 1999 ), granulosa cells (Tilly et al., 1995 ) and luteal tissue (Goodman et al., 1998 ) is known to be actively repressed by the presence of cell survival-promoting hormones in vivo and in vitro.
Ovarian localization Primordial Germ Cell, Oocyte, Granulosa, Luteal cells
Comment Bid and Bax Are Involved in Granulosa Cell Apoptosis During Follicular Atresia in Porcine Ovaries. Sai T et al. More than 99% of follicles undergo 'atresia' during follicular development and growth. Follicular atresia is predominantly regulated by granulosa cell apoptosis. However, theintracellular signaling pathway of apoptosis in granulosa cells has not been revealed. In the present study, we examined changes in the expression of BH3-interacting domain death agonist (Bid) and Bcl-2-associated X protein (Bax), which are considered to promote the cell death ligand/receptor- mediated process in mitochondrion-dependent type II apoptosis, in porcine granulosa cells during atresia. Levels of mRNA and protein of Bid and Bax were determined by the reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting techniques, respectively. Levels of Bid and Bax mRNA and protein were markedly increased in granulosa cells of early atretic follicles compared with those of healthy follicles. In situ hybridization and immunohistochemical staining revealed that mRNA and protein of Bid and Bax were present in the granulosa cells, though only traces were found in healthy follicles; however, strong staining was noted in atretic follicles. These results indicate that Bid and Bax appear to be signal transduction factors in granulosa cells during follicular atresia and appear to play proapoptotic roles and confirm that the porcine granulosa cell is a mitochondrion-dependent type II apoptotic cell. Messenger RNA encoding Bax has been localized in rat granulosa cells, mouse oocytes, human luteinizing granulosa cells, bovine corpora lutea, and rabbit corpora lutea. Bax protein has been localized in mouse oocytes and human granulosa cells (for details, see references provided in previous section). Norihiro Sugino, et al reported the expression of Bcl-2 and Bax in the Human Corpus Luteum during the Menstrual Cycle and in Early Pregnancy and Regulation by Human Chorionic Gonadotropin. Immunohistochemistry revealed that Bcl-2 expression was observed in the luteal cells in the midluteal phase and early pregnancy, but not in the regressing CL. In contrast, Bax immunostaining was observed in the regressing CL, but not in the midluteal phase and early pregnancy. Bcl-2 messenger ribonucleic acid (mRNA) levels in the CL during the menstrual cycle were highest in the midluteal phase and lowest in the regressing CL. In the CL of early pregnancy, bcl-2 mRNA levels were significantly higher than those in the midluteal phase. In contrast, bax mRNA levels were highest in the regressing CL and remarkably low in the CL of early pregnancy. When corpora lutea of the midluteal phase were incubated with hCG, hCG significantly increased the mRNA and protein levels of Bcl-2 and significantly decreased those of Bax.
Follicle stages Primordial, Primary, Antral, Preovulatory, Corpus luteum
Comment The functional significance of Bax in normal follicular dynamics has been clearly established by analysis of multiple ovarian defects in bax gene knockout female mice. These include a significantly reduced rate of primordial and primary follice atresia due to defects in oocyte apoptosis (Perez et al., 1999 ), aberrant maturing follicle atresia due to an apparent defect in granulosa cell apoptosis (Knudson et al., 1995 ), and a prolongation of functional ovarian lifespan into very advanced chronological age (Perez et al., 1999 ).
Phenotypes
Mutations

Species: mouse - bax gene disruption
type: null mutation
fertility: subfertile
Comment: Original report of targeted disruption of the bax gene in mice was made in 1995 (Knudson et al., 1995 ). Among mutiple phenotypes reported, Bax-deficient male mice exhibit sterility and Bax-deficient female mice exhibit defective follicle atresia.
See comments and references above for impact of bax null mutation on normal ovarian germ cell and follicle dynamics. In addition, Bax-deficiency in mouse oocytes conveys resistance to chemotherapy-induced apoptosis in vivo and in vitro (Perez et al., 1997 ). Switch from BAX-dependent to BAX-independent germ cell loss during the development of fetal mouse ovaries. Alton M et al. Female reproductive life is limited by the oocyte/follicle pool, which has been determined by the number of germ cells to enter meiosis and subsequent loss of oocytes. It has been suggested that apoptosis accounts for the elimination of germ cells throughout oogenesis. However, female germ cells are lost continuously while they undergo distinct cell cycles in fetal and neonatal life. No convincing evidence has yet been provided to show apoptotic death of oocytes during meiotic prophase in vivo. In this study, we examined the change in the germ cell population in mice deficient of BAX, a key proapoptotic molecule. The number of germ cells, identified by GCNA1 immunolabeling, approximately doubled in ovaries of Bax(-/-) mice compared with ovaries of heterozygous Bax(+/-) mice and wild-type Bax(+/+) mice by 14.5 days post coitum (d.p.c.) and remained higher up to 24.5 d.p.c. However, there was a rapid loss of germ cells in Bax(-/-) ovaries, paralleling that in Bax(+/-) and Bax(+/+) ovaries from 14.5-24.5 d.p.c., a period in which most germ cells entered and progressed in meiotic prophase. These results suggest that, while progressing through meiotic prophase, oocytes are eliminated by a BAX-independent mechanism.

Species: human - somatic bax gene frameshift
type: naturally occurring
fertility: unknown
Comment: Missense somatic mutation of Bax is associated with tumorigenesis as the result of prolonged survival of affected cells. Frameshift mutations in both alleles of the human bax gene have been identified in some microsatellite mutator phenotype colon adenocarcinomas (Rampino et al., 1997 . It was speculated that inactivating bax gene mutations may be selected for during progression of human colon cancer.

Species: mouse -
type: null mutation
fertility: fertile
Comment: BAX regulates follicular endowment in mice. Greenfeld CR et al. It is believed that the endowment of primordial follicles in mammalian ovaries is finite. Once follicles are depleted, infertility ensues. Thus, the size of the initial endowment has consequences for fertility and reproductive longevity. Follicular endowment is comprised of various processes that culminate with the incorporation of meiosis-arrested oocytes into primordial follicles. Apoptosis is prominent during follicular endowment, and apoptosis regulatory genes are involved in its regulation. Conflicting data exist with regard to the role of the proapoptotic Bcl-2 associated X protein (BAX) in follicular endowment. Therefore, we investigated the role of BAX during follicular endowment in embryonic and neonatal ovaries. We found that BAX is involved in regulating follicular endowment in mice. Deletion of Bax yields increased oocyte numbers in embryonic ovaries and increased follicle numbers in neonatal ovaries when compared with wild-type ovaries. Increased follicular endowment in Bax-/-ovaries is not due to enhanced germ cell viability. Further, it is not due to an increased primordial germ cell (PGC) allotment, a delay in the onset of meiosis, or altered proliferative activity of oogonia. Instead, our data suggest that the regulatory activity of BAX in follicular endowment likely occurs during PGC migration, prior to PGC colonization of the gonad.

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created: 2000-04-06 00:00:00 by: Jonathan L. Tilly, Harvard Medical School, Massachusetts General Hospital   email: jtilly@partners.org
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last update: 2011-11-05 08:22:54 by: Aaron J Hsueh, hsuehlab   email: aaron.hsueh@stanford.edu



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