Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.22.36 (caspase-1)
 6,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Caenorhabditis elegans death susceptibility gene, ced-3, has a number of homologs in vertebrate species, including interleukin-1 beta (IL-1 beta)-converting enzyme (ICE), Ich-1long, and CPP32. These genes, which encode a family of related proteases, have been shown to induce apoptosis when transfected into eukaryotic cells. However, it remains to be determined whether these proteases are involved in apoptotic cell death under physiological conditions. The purpose of these studies was to examine the role of ICE-related proteases (IRPs) in apoptosis using a physiologically relevant model system, the ovarian follicle. Somatic granulosa cells within ovarian follicles undergo apoptosis during follicular atresia, a process responsible for the depletion of greater than 95% of the follicles established in the postnatal ovary. To accomplish these studies, we cloned partial rat complementary DNAs encoding ICE, Ich-1, and CPP32 and used these complementary DNAs to examine the gonadotropin regulation of ICE, Ich-1, and CPP32 gene expression in the immature rat ovary. We also examined levels of ICE activity in healthy and atretic rat follicles by monitoring the conversion of exogenous pro-IL-1 beta to the active cytokine, and then evaluated the actions of recombinant IL-1 beta on apoptosis in follicles incubated in vitro. Finally, we tested the requirement for IRP activity in granulosa cell apoptosis and follicular atresia by incubating follicles without and with IRP inhibitors. Northern blot analysis of total RNA samples indicated that gonadotropin-promoted follicular survival was associated with reduced ovarian expression of messenger RNAs encoding Ich-1 and CPP32. In contrast, ICE messenger RNA levels were extremely low and were not affected by gonadotropin treatment. We were also unable to detect ICE activity in proteins extracted from either healthy or atretic rat follicles, collectively suggesting that ICE per se may not function in granulosa cell death. As another approach to determine whether ICE is involved in atresia, healthy antral follicles were isolated from ovaries of gonadotropin-primed immature rats and incubated for 24 h in the absence or presence of 100 ng/ml transforming growth factor-alpha (TGF alpha) without and with 100 ng/ml IL-1 beta. Granulosa cells within follicles incubated in medium alone exhibited extensive levels of apoptosis, and this onset of apoptosis was prevented by the inclusion of TGF alpha. Addition of IL-1 beta did not alter basal levels of apoptosis nor did the cytokine antagonize TGF-alpha-promoted follicle survival, providing additional evidence that ICE activity is not required for atresia to occur.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Interleukin-1 beta-converting enzyme-related proteases (IRPs) and mammalian cell death: dissociation of IRP-induced oligonucleosomal endonuclease activity from morphological apoptosis in granulosa cells of the ovarian follicle. 758 40

Apoptosis is an important cellular process by which superfluous or unwanted cells are deleted from an organism during tissue remodeling and differentiation. Recent studies have demonstrated the role of this programmed cell death or "controlled cell suicide" in the physiological function of an organism. Suppression of apoptosis increases the susceptibility of an individual to malignancy whereas uncontrolled cell death is associated with degenerative diseases. Normal development of both female and male gonads is characterized by massive cell death. More than 99% of ovarian follicles endowed at early life are destined to undergo apoptosis and the exhaustion of these follicles serves as a "clock" for female reproductive senescence. In the testis, up to 75% of male germ cells also undergo apoptosis, perhaps as a mechanism to delete superfluous or defective germ cells. Gonadal cell apoptosis provides valuable models to study hormonal regulation of apoptosis. In the ovary, gonadotropins, estrogens, growth hormone, growth factors (IGFI, EGF/TGF-alpha, basic FGF), cytokine (interleukin-1 beta) and nitric oxide act in concert to ensure the survival of preovulatory follicles. In contrast, androgens, interleukin-6 and gonadal GnRH-like peptide are apoptotic factors. Developmental studies further indicate that fractions of endowed follicles are recruited throughout the reproductive life whereas most of the primordial follicles are "arrested" at the initial stage of development for a prolonged time. Because a transcriptional factor WT1 is expressed in high levels in follicles at early stages of development and because WT1 over-expression represses the promoter activity of inhibin-alpha gene, this nuclear protein may be important in the maintenance of follicles at early stages of development. Once a cohort of follicles is recruited to grow, it is destined to undergo apoptosis unless rescued by survival factors. After puberty onset and under gonadotropin stimulation, some of the growing antral follicles are "selected" to continue their final maturation and secrete high levels of estrogens to trigger ovulation. Following repeated cycles of recruitment, atresia or ovulation, the follicle reserve is exhausted, thus signaling the onset of reproductive senescence. Although the somatic granulosa cell is the major cell type undergoing apoptosis in the ovary, the germ cells in the testis also exhibit signs of apoptotic cell demise. In the testis, gonadotropins and androgens act as survival factors whereas exposure to elevated temperature in cryptorchid testes increases apoptosis. In the seasonally breeding hamster model, photoperiod-entrained regression and recrudescence of testis tissue serves as a unique natural model of apoptosis. With recent advances in our understanding of the cellular mechanism of apoptosis, including the elucidation of the Ced9/bc12 and Ced3/ICE family of proteins, further investigation of gonadal apoptosis may lead to a better understanding of gonadal degenerative disorders (such as premature ovarian failure and oligospermia), reproductive senescence and tumorigenesis. The gonadal model should also be valuable in studying the regulation of intracellular apoptosis genes by external hormonal signals.
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PMID:Gonadal cell apoptosis. 870 Oct 90

The majority of ovarian follicles undergo atresia, a hormonally controlled apoptotic process. Monitoring apoptotic DNA fragmentation provides a quantitative and sensitive endpoint to study the hormonal regulation of atresia in ovarian follicles. During follicle development, gonadotropins, together with local ovarian growth factors (IGF-I, EGF/TGF-alpha, basic FGF) and cytokine (interleukin-1 beta), as well as estrogens, activate different intracellular pathways to rescue follicles from apoptotic demise. In contrast, TNF-alpha, Fas ligand, presumably acting through receptors with a death domain, and androgens are atretogenic factors. These diverse hormonal signals probably converge on selective intracellular pathways (including genes of the bcl-2 and ICE families) to regulate apoptosis. With a constant loss of follicles from the original stockpile, the ovary provides a unique model for studying the hormonal regulation of apoptosis.
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PMID:Regulation of ovarian follicle atresia. 907 68