The
predicted 440-amino acid protein of TRAILR2 contains a putative signal peptide, 2 cysteine-rich pseudorepeats characteristic of TNF
receptor (TNFR) family members, a transmembrane domain, and an intracellular death domain. The death domain of
TRAILR2 shares 30% identity with that of TNFR1 (OMIM 191190). Overall, the TRAIL receptors TRAILR2 and TRAILR1 (DR4;
OMIM 603611) are 58% identical. As with TRAILR1, overexpression of TRAILR2 engaged a caspase-dependent apoptotic
pathway. However, in contrast to TRAILR1, TRAILR2 mediated apoptosis via the intracellular adaptor molecule FADD
. Northern blot analysis indicated that TRAILR2 was expressed as a 4.4-kb mRNA in all tissues tested, with the
highest levels of expression in peripheral blood lymphocytes, spleen, and ovary.
General function
Receptor
Comment
Cellular localization
Plasma membrane
Comment
Ovarian function
Follicle atresia
Comment
Bridgham JT, et al 2002 reported TVB (DR5-like) death receptor expression in hen ovarian
follicles.
TVB is an avian death domain-containing receptor belonging to the TNF receptor
family and is proposed to be the ortholog to mammalian DR5. Although TVB receptor
activation has been demonstrated to mediate apoptosis in chick embryo fibroblasts,
there is essentially no information regarding TVB expression or regulation in the
mature hen ovary, and in particular within the follicle granulosa layer where
apoptosis is known to promote atresia. Significantly, the TVB receptor represents the
fourth death domain-containing receptor (also including Fas, TNF-R1, and DR6)
found to be expressed within hen granulosa cells. Levels of TVB expression are
higher in prehierarchal follicles actively undergoing atresia compared to healthy
follicles. However, increased TVB expression does not precede follicle death
induced in vitro. Furthermore, TVB expression within granulosa cells is highest
during the final stages of follicle development when follicles are not normally
susceptible to undergoing atresia. These results provide evidence that TVB receptor
signaling in the ovary may function in a capacity other than solely to mediate
granulosa cell death and follicle atresia.
Expression regulated by
Comment
Ovarian localization
Oocyte, Granulosa
Comment
TRAIL pathway components and their putative role in granulosa cell apoptosis in the human ovary. Jskelinen M et al. Extensive apoptotic oocyte reduction occurs during fetal ovarian development. The regulatory pathways responsible for oocyte selection to programmed cell death are, however, poorly understood. The aim of this study was to investigate the potential involvement of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its death receptors TRAIL-R1/DR4 and TRAIL-R2/DR5 and decoy receptors TRAIL-R3/DcR1 and TRAIL-R4/DcR2 in the apoptotic process characterizing human fetal and adult ovaries. For this purpose, in situ hybridization and immunohistochemistry were applied to human fetal and adult ovarian samples to study the mRNA and protein expression of TRAIL pathway components, and a human granulosa cell tumor-derived cell line (KGN) was used to elucidate functional effects of TRAIL on apoptosis. TRAIL was expressed in human fetal ovary from the 11th week until term. The pro-apoptotic TRAIL-R2/DR5 and the anti-apoptotic TRAIL-R4/DcR2 were also expressed in human ovaries throughout the fetal period. Among the different ovarian cell types, these TRAIL pathway components were mainly localized in the oocytes, and their expression increased towards term. Expression of TRAIL-R1/DR4 and TRAIL-R3/DcR1 was negligible in all of the fetal ovaries studied. Adult ovaries expressed TRAIL, TRAIL-R2/DR5, TRAIL-R3/DcR1 and TRAIL-R4/DcR2 in granulosa cells and oocytes of small primary/secondary follicles as well as in granulosa and theca cells of more developed antral follicles. In KGN cells, TRAIL efficiently induced apoptosis in a dose-dependent manner, and this was blocked by a caspase inhibitor. The results indicate a role of the TRAIL pathway components in the regulation of granulosa cell apoptosis in in vitro and suggest that these factors may have a role in regulating ovarian apoptosis also in vivo.