The inhibitor of apoptosis proteins (IAPs) constitute a family of highly conserved apoptosis suppressor proteins that was originally identified in baculoviruses. Rothe et al. (1995) identified and cloned HIAP2 (and HIAP1), which interact with TNFR2 (tumor necrosis factor receptor-2); HIAP2 (and HIAP1) do not directly contact TNFR2, but rather associate with TRAF1 and TRAF2 (tumor necrosis factor receptor-associated factors) through their N-terminal BIR (baculoviral inhibition of apoptosis protein repeat) domain. The recruitment of HIAP2 (or HIAP1) to the TNFR2 signaling complex requires a TRAF2-TRAF1 heterocomplex. HIAP2 shares 72% and 42% identity with HIAP1 and XIAP, respectively (Liston et al., 1996) MIHB/HIAP2 and MIHC (mammalian IAP homolog C) share 73% identity (Uren et al., 1996). McCarthy et al. (1998) found that in Drosophila, Reaper- or Grim-induced apoptosis in mammalian cells was inhibited by a broad range of caspase inhibitors and by human inhibitor of apoptosis proteins HIAP2 and HIAP1, whereby Grim and Reaper were bound to the IAPs. HIAP2 and HIAP1 are direct inhibitors caspase-3 and caspase-7; HIAP2 and HIAP1 can prevent the proteolytic processing of pro-caspases -3, -6 and -7 by blocking the cytochrome c-induced activation of pro-caspase-9. In contrast, these IAP family proteins do not prevent caspase-8-induced proteolytic activation of pro-caspase-3; however, they do subsequently inhibit active caspase-3 directly, thus blocking downstream apoptotic events such as further
activation of caspases. These findings demonstrate that IAPs can suppress different apoptotic pathways by inhibiting distinct caspases and identify pro-caspase-9 as a new target for IAP-mediated inhibition of apoptosis.
NCBI Summary:
The protein encoded by this gene is a member of a family of proteins that inhibits apoptosis by binding to tumor necrosis factor receptor-associated factors TRAF1 and TRAF2, probably by interfering with activation of ICE-like proteases. BIRC2 inhibits apoptosis induced by serum deprivation and menadione, a potent inducer of free radicals. The amino acid sequence predicts three baculovirus IAP repeat domains and a ring finger domain.
General function
Cell death/survival, Metabolism
Comment
Uren et al. (1996) determined that expression of MIHB in mammalian cells significantly reduces apoptosis mediated by ICE (interleukin 1beta converting enzyme). They stated that the ability of MIHB to bind TRAFs suggested that MIHB may inhibit apoptosis by regulating signals required for activation of ICE-like proteases.
HIAP2 and XIAP expression in both granulosa and theca cells increased with follicular maturation, reaching maximal levels at the antral stage of development. XIAP and HIAP2 decreased markedly in atretic follicles at the small to medium sized antral stage of development, suggesting follicular atresia may be associated with decreased granulosa cell IAP protein content
and decreased proliferation. DNA fragmentation in granulosa cells from preantral and early antral follicles indicates extensive apoptosis associated with minimal IAP protein content. IAPs may be involved in the suppression of granulosa cell apoptosis by gonadotropin in small to medium-sized antral follicles and play an important role in determining the fate of the cells, and thus also the eventual follicular destiny (atresia vs. ovulation) (Li et al.,1998).
Expression regulated by
FSH, LH
Comment
Gonadotropin treatment increases HIAP2 and XIAP protein content and suppresses apoptosis in granulosa cells, resulting in the development of follicles to the antral and preovulatory stages. In addition, gonadotropin withdrawal induces apoptotic DNA fragmentation in granulosa cells in early antral and antral follicles, which is accompanied by a marked decrease in HIAP2 and XIAP expression (Li et al.,1998).
Ovarian localization
Granulosa, Theca
Comment
Follicle stages
Antral, Preovulatory
Comment
An increase in HIAP2 following gonadotropin treatment increases HIAP2 protein content and suppresses apoptosis in granulosa cells, resulting in the development of follicles to the antral and preovulatory stages (Li et al.,1998).