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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The p53 tumor suppressor gene is thought to be required for the induction of programmed cell death (apoptosis) initiated by DNA damage. We show here, however, that the human promyelocytic leukemia cell line HL-60, which is known to be deficient in p53 because of large deletions in the p53 gene, can be induced to undergo apoptosis following X-irradiation. We demonstrate that the decision to undergo apoptosis in this cell line appears to be made at a G2 checkpoint. In addition, we characterize an HL-60 variant, HCW-2, which is radioresistant. HCW-2 cells display DNA damage induction and repair capabilities identical to those of the parental HL-60 cell line. Thus, the difference between the two cell lines appears to be that X-irradiation induces apoptosis in HL-60, but not in HCW-2, cells. Paradoxically, HCW-2 cells display high levels of expression of bax, which enhances apoptosis, and no longer express bcl-2, which blocks apoptosis. HCW-2 cells' resistance to apoptosis may be due to the acquisition of expression of bcl-XL, a bcl-2-related inhibitor of apoptosis. In summary, apoptosis can be induced in X-irradiated HL-60 cells by a p53-independent mechanism at a G2 checkpoint, despite the presence of endogenous bcl-2. The resistance shown by HCW-2 cells suggests that bcl-XL can block this process.
Mol Cell Biol 1995 Nov
PMID:Evidence for a G2 checkpoint in p53-independent apoptosis induction by X-irradiation. 756 37

The SF-21 insect cell line undergoes rapid and widespread apoptosis when treated with actinomycin D or when infected with a mutant of the baculovirus Autographa californica nuclear polyhedrosis virus lacking a p35 gene or a functionally active iap (inhibitor of apoptosis) gene. Here we provide evidence that the basis for the induction of apoptosis by these two different stimuli is the cessation of RNA synthesis. We also show that expression of either p35 or two different functional iap homologs blocks apoptosis independently of other viral genes, indicating that these gene products act directly on the cellular apoptotic pathway. The iap genes encode a C3HC4 (or RING) finger motif found in a number of transcriptional regulatory proteins, as well as two additional Cys/His motifs (baculovirus iap repeats). We show that specific amino acids within both the C3HC4 finger and the N-terminal baculovirus iap repeat are critical for anti-apoptosis function. Overexpression of either mammalian bcl-2 or adenovirus E1B-19K, genes which block apoptosis when overexpressed in a number of mammalian cells, does not block actinomycin D-induced apoptosis in SF-21 cells.
Mol Cell Biol 1994 Aug
PMID:Control of programmed cell death by the baculovirus genes p35 and iap. 803

DNA fragmentation in murine monocytes and freshly harvested resident peritoneal macrophages (RPM) was assessed. Similar proportions of fragmented DNA were present in both cell types indicating that apoptosis is a significant occurrence in these cells and may provide a mechanism for controlling the numbers of mononuclear phagocytes in the tissues that house them. Culturing both of these cell types at 41 degrees C for 5 hr revealed a significant increase in the proportion of fragmented DNA only in cultures containing RPM. These latter preparations when cytophotometrically assessed also displayed reduced Feulgen DNA and cytoplasmic naphthol yellow S staining, again confirming the presence of apoptosis. It is suggested that the induction of apoptosis by mild hyperthermia may therefore be due to the relative absence of a temperature-sensitive inhibitor of apoptosis in a significant proportion of resident peritoneal macrophages. Lastly, electron microscope assessment indicated that the apoptotic macrophages were engulfed by their nonaffected neighbors. Programmed cell death in macrophage populations followed by phagocytosis of the apoptotic cells may therefore be a mechanism for controlling macrophage numbers in mammalian organisms.
Exp Mol Pathol 1993 Aug
PMID:Quantitative investigations of apoptosis of murine mononuclear phagocytes during mild hyperthermia. 826 61

Reaper (RPR), HID, and GRIM activate apoptosis in cells programmed to die during Drosophila development. We have previously shown that transient overexpression of RPR in the lepidopteran SF-21 cell line induces apoptosis and that members of the inhibitor of apoptosis (IAP) family of antiapoptotic proteins can inhibit RPR-induced apoptosis and physically interact with RPR through their BIR motifs (D. Vucic, W. J. Kaiser, A. J. Harvey, and L. K. Miller, Proc. Natl. Acad. Sci. USA 94:10183-10188, 1997). In this study, we found that transient overexpression of HID and GRIM also induced apoptosis in the SF-21 cell line. Baculovirus and Drosophila IAPs blocked HID- and GRIM-induced apoptosis and also physically interacted with them through the BIR motifs of the IAPs. The region of sequence similarity shared by RPR, HID, and GRIM, the N-terminal 14 amino acids of each protein, was required for the induction of apoptosis by HID and its binding to IAPs. When stably overexpressed by fusion to an unrelated, nonapoptotic polypeptide, the N-terminal 37 amino acids of HID and GRIM were sufficient to induce apoptosis and confer IAP binding activity. However, GRIM was more complex than HID since the C-terminal 124 amino acids of GRIM retained apoptosis-inducing and IAP binding activity, suggesting the presence of two independent apoptotic motifs within GRIM. Coexpression of IAPs with HID stabilized HID levels and resulted in the accumulation of HID in punctate perinuclear locations which coincided with IAP localization. The physical interaction of IAPs with RPR, HID, and GRIM provides a common molecular mechanism for IAP inhibition of these Drosophila proapoptotic proteins.
Mol Cell Biol 1998 Jun
PMID:Inhibitor of apoptosis proteins physically interact with and block apoptosis induced by Drosophila proteins HID and GRIM. 958 70

The adenovirus E1B 19,000-molecular-weight (19K) protein is a potent inhibitor of apoptosis and cooperates with E1A to transform primary rodent cells. E1B 19K shows sequence and functional homology to the mammalian antiapoptotic gene product, Bcl-2. Like Bcl-2, the biochemical mechanism of E1B 19K function includes binding to and antagonization of cellular proapoptotic proteins such as Bax, Bak, and Nbk/Bik. In addition, there is evidence that E1B 19K can affect gene expression, but whether this contributes to its antiapoptotic function has not been determined. In an effort to further understand the functions of E1B 19K, we screened for 19K-associated proteins by the yeast two-hybrid system. A novel protein, Btf (Bcl-2-associated transcription factor), that interacts with E1B 19K as well as with the antiapoptotic family members Bcl-2 and Bcl-xL but not with the proapoptotic protein Bax was identified. btf is a widely expressed gene that encodes a protein with homology to the basic zipper (bZip) and Myb DNA binding domains. Btf binds DNA in vitro and represses transcription in reporter assays. E1B 19K, Bcl-2, and Bcl-xL sequester Btf in the cytoplasm and block its transcriptional repression activity. Expression of Btf also inhibited transformation by E1A with either E1B 19K or mutant p53, suggesting a role in either promotion of apoptosis or cell cycle arrest. Indeed, the sustained overexpression of Btf in HeLa cells induced apoptosis, which was inhibited by E1B 19K. Furthermore, the chromosomal localization of btf (6q22-23) maps to a region that is deleted in some cancers, consistent with a role for Btf in tumor suppression. Thus, btf may represent a novel tumor suppressor gene residing in a unique pathway by which the Bcl-2 family can regulate apoptosis.
Mol Cell Biol 1999 Jun
PMID:Btf, a novel death-promoting transcriptional repressor that interacts with Bcl-2-related proteins. 1033 Jan 79

Effects of selenite and selenodiglutathione, an initial metabolite of selenite, on the induction of apoptosis and cytotoxicity were investigated in human promyelocytic leukemia HL-60 cells. Treatment of selenite or selenodiglutathione resulted in concentration-dependent cytotoxicity, measured by lactate dehydrogenase leakage assay, and by tetrazolium salt reduction assay. Selenodiglutathione has been shown to exert more cytotoxic effect than selenite in both assay systems. Time-course study of cellular selenium uptake suggests that the higher cytotoxicity of selenodiglutathione be largely due to faster and greater selenium uptake rate. Treatment with selenite or selenodiglutathione also induced apoptosis in a dose-dependent manner, as detected by enzyme-linked immunosorbent assay and by DNA fragmentation assay. The dose-response data of apoptosis induced by selenite or selenodiglutathione were similar to those of cytotoxicity, implicating a relationship between the induction of apoptosis and cytotoxicity. Zn, which is a well-known inhibitor of apoptosis, dose-dependently blocked not only the induction of apoptosis, but also the membrane damage induced by selenium, corroborating this hypothesis. It was noted that the inhibition of apoptosis by Zn exerted little protective effect on cytotoxicity at higher concentrations of selenium, compared with a perfect protective effect at low concentration of selenium. These results suggest that cytotoxicity induced by selenium may be partially correlated with apoptosis.
Biochem Mol Biol Int 1999 May
PMID:Induction of apoptosis by selenite and selenodiglutathione in HL-60 cells: correlation with cytotoxicity. 1036 49

A stable transfectant (S2SN7) of p53-null SaOS-2 (human osteosarcoma) cells expressing wild-type p53 under the tight control of a tetracycline-responsive promoter was used to study the functional roles of p53 in cellular response to cisplatinum (CP). When cells were grown in media containing normal concentrations (10%) of serum, induction of p53 by tetracycline withdrawal resulted in an 8-fold decrease in sensitivity to CP. In contrast, when cells were grown in lower serum (1%) media, induction of p53 led to a 10-fold increase in sensitivity to CP. The p53-mediated sensitivity to CP under lower serum conditions was attributed, at least in part, to increased susceptibility of p53-mediated apoptosis. Under lower serum (0.1-1%) but not normal serum conditions, p53 induction correlated with selective down-regulation of bcl-2, an inhibitor of apoptosis. In addition, a host-cell reactivation assay showed that induction of p53 caused a significant increase in repair of CP-induced DNA damage under normal serum but not low serum conditions. These data suggest that growth conditions may modulate and possibly reverse p53-mediated CP sensitivity by altering p53-mediated gene regulation and, as a result, susceptibility to apoptosis. They also suggest that a combined effect of p53-mediated apoptosis and DNA repair may be the ultimate determinant in p53-mediated cellular resistance or sensitivity to chemotherapeutic drugs.
Mol Pharmacol 1999 Nov
PMID:Modulation of cisplatinum cytotoxicity by p53: effect of p53-mediated apoptosis and DNA repair. 1053 2

Tumor necrosis factor (TNF) receptor (TNFR)-associated factors 1 and 2 (TRAF1 and TRAF2) and inhibitor of apoptosis proteins cIAP1 (MIHB) and cIAP2 (MIHC) were recently identified as proteins that associate with the TNF-alpha receptors TNFRI (p55) and TNFRII (p75) and inhibit TNF-alpha-induced programmed cell death or apoptosis. In the original reports, TRAF1 expression, unlike the ubiquitous TRAF2, was restricted to specific tissues in the lung, spleen, and testis. TNF-alpha is increased in the lung in many forms of pulmonary disease. In the current study, Western analysis, immunohistochemistry, and ribonuclease protection assays were used to determine whether TNF-alpha regulates the expression of these TNFR-associated proteins in lung cells. We demonstrate for the first time TNF-alpha dose-dependent induction of TRAF1 protein and messenger RNA (mRNA) in human H441 and A549 pulmonary adenocarcinoma cell lines, as well as in lung cells of C57BL/6J mice after intratracheal administration of TNF-alpha. In contrast to the epithelial cells, TRAF1 was not induced by TNF-alpha in U937 cells, a human monocytic cell line, suggesting cell type-specific regulation. Similarly, cIAP2 mRNA was induced by TNF-alpha in both H441 and A549 pulmonary epithelial cells but not in U937 cells. TNF-alpha is a primary mediator of acute pulmonary inflammation and contributes to the pathophysiology of chronic lung diseases such as bronchopulmonary dysplasia (BPD), a fibrotic disease of prematurely born infants. Immunohistochemical staining of human neonatal lung tissue demonstrated increased TRAF1 in lungs of infants dying of pneumonia or BPD in comparison with those dying of congenital malformation. These studies support the hypothesis that the TRAF1 and cIAP2 genes are highly regulated in pulmonary cells and may play a role in human lung disease.
Am J Respir Cell Mol Biol 2000 Feb
PMID:Tumor necrosis factor-alpha-induced lung cell expression of antiapoptotic genes TRAF1 and cIAP2. 1065 35

The defining structural motif of the inhibitor of apoptosis (iap) protein family is the BIR (baculovirus iap repeat), a highly conserved zinc coordination domain of approximately 70 residues. Although the BIR is required for inhibitor-of-apoptosis (IAP) function, including caspase inhibition, its molecular role in antiapoptotic activity in vivo is unknown. To define the function of the BIRs, we investigated the activity of these structural motifs within Op-IAP, an efficient, virus-derived IAP. We report here that Op-IAP(1-216), a loss-of-function truncation which contains two BIRs but lacks the C-terminal RING motif, potently interfered with Op-IAP's capacity to block apoptosis induced by diverse stimuli. In contrast, Op-IAP(1-216) had no effect on apoptotic suppression by caspase inhibitor P35. Consistent with a mechanism of dominant inhibition that involves direct interaction between Op-IAP(1-216) and full-length Op-IAP, both proteins formed an immunoprecipitable complex in vivo. Op-IAP also self-associated. In contrast, the RING motif-containing truncation Op-IAP(183-268) failed to interact with or interfere with Op-IAP function. Substitution of conserved residues within BIR 2 caused loss of dominant inhibition by Op-IAP(1-216) and coincided with loss of interaction with Op-IAP. Thus, residues encompassing the BIRs mediate dominant inhibition and oligomerization of Op-IAP. Consistent with dominant interference by interaction with an endogenous cellular IAP, Op-IAP(1-216) also lowered the survival threshold of cultured insect cells. Taken together, these data suggest a new model wherein the antiapoptotic function of IAP requires homo-oligomerization, which in turn mediates specific interactions with cellular apoptotic effectors.
Mol Cell Biol 2000 Mar
PMID:The BIR motifs mediate dominant interference and oligomerization of inhibitor of apoptosis Op-IAP. 1066 62

Survivin is a novel inhibitor of apoptosis. It has been reported that survivin is expressed during fetal development and in cancer tissues, but its expression has not been reported in adult tissues. We investigated the expression of survivin in the endometria of women with regular menstrual cycles using reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry, and compared these findings with Bcl-2, an apoptosis inhibitor. Survivin mRNA was detected by RT-PCR in all samples (nine of nine) of endometrium during the secretory phase, but in only four out of seven samples from endometrium during the proliferative phase, and in none of the atrophic endometrium. Immunohistochemistry demonstrated a survivin protein expression that was strongest in the nuclei of glandular epithelial cells during the late secretory phase. In the proliferative phase, glandular epithelial cells were not stained for survivin. The cyclic changes of survivin and Bcl-2 showed an inverse relationship, with Bcl-2 expression being strongest in the proliferative phase and survivin expression being strongest in the secretory phase. The up-regulation of survivin expression may be due to the concurrent rise in progesterone concentrations during the normal menstrual cycle. Moreover, survivin could play an important role independent of Bcl-2 in physiological homeostasis in the normal endometrium.
Mol Hum Reprod 2000 Jun
PMID:Expression of survivin and Bcl-2 in the normal human endometrium. 1082 70


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