Disease relevance of PMAIP1

• We show that Noxa promoter responds directly to hypoxia via hypoxia-inducible factor (HIF)-1alpha [1].
• Suppression of Noxa expression by antisense oligonucleotides rescued cells from hypoxia-induced cell death and decreased infarction volumes in an animal model of ischemia [1].
• Ectopic expression of Noxa in HT1080 fibrosarcoma cells enhanced cellular sensitivity to viral or dsRNA/actinomycin D-induced apoptosis, typified by enhanced cytochrome c release from the mitochondrial to the cytosolic fraction and increased cleavage of caspases 3 and 9 [2].
• Noxa in colorectal cancer: a study on DNA, mRNA and protein expression [3].
• We have investigated the mRNA expression of Noxa with real-time PCR in 94 unselected colorectal adenocarcinomas and the corresponding normal mucosa [3].

Psychiatry related information on PMAIP1

• Because food deprivation is associated with an impaired APR, food restriction may prevent these beneficial changes [4].
• In previous publications, we presented the hypothesis that repeated episodes of acute or chronic psychological stress could induce an acute phase response (APR) and subsequently a chronic inflammatory process such as atherosclerosis [5].
• In undifferentiated THP-1 cells, low CD4 expression significantly reduced the susceptibility of the cells to infection with the R5 HIV-1(BaL) isolate, whereas a PMA-induced decrease in CD4 expression reduced permissiveness of the cells to the X4 HIV-1(IIIB) isolate [6].

High impact information on PMAIP1

• The impaired tumor development correlated with increased levels of p53 and its target gene noxa, resulting in the induction of apoptosis without affecting cell proliferation [7].
• While studying the mitogenic properties of one of these agents, phorbol myristate acetate (PMA), we found that dimethyl sulphoxide (DMSO), frequently used as a solvent for PMA, markedly inhibits PMA-induced mitogenesis at DMSO concentrations that have little effect on phytohaemagglutinin (PHA)-induced responses [8].
• We report here that many of the compounds that induce erythroid differentiation in FL cells are similar to DMSO in selectively suppressing PMA-induced lymphocyte mitogenesis [8].
• Bim and Puma bind all the pro-survival proteins, whereas others, such as Noxa and Bad, engage distinct subsets and exhibit complementary killing [9].
• Accordingly, the BH3-only protein Noxa could bind to Mcl-1, displace Bak, and promote Mcl-1 degradation, but Bak-mediated cell death also required neutralization of Bcl-x(L) by other BH3-only proteins [10].

Chemical compound and disease context of PMAIP1

• Using polymerase chain reaction-based suppression subtractive hybridization to find genes that are differentially expressed in hypoxia, we identified the BH3-only Bcl-2 family protein Noxa [1].
• Together, these studies suggest that Phenoxodiol induces apoptosis of melanoma cells by induction of p53-dependent BH3 proteins (Bad, PUMA and Noxa) and the p53-independent Bim protein, resulting in activation of Bax and its downstream events [11].
• To enhance the bortezomib-mediated killing of melanoma cells, the apoptotic pathway involving NOXA was further investigated, leading to identification of an important target (i.e., the labile Bcl-2 homologue Mcl-1 but not other survival proteins) [12].
• These observations suggest the possible role of sphingosine in induction of apoptotic DNA fragmentation during PMA-induced differentiation in myeloid leukemia cells [13].
• By simultaneously triggering production of NOXA (using bortezomib) as well as reducing Mcl-1 levels (using siRNA, UV light, or fludarabine), significantly enhanced killing of melanoma cells was achieved [12].

Biological context of PMAIP1

• BOK and NOXA are essential mediators of p53-dependent apoptosis [14].
• When cytotoxic signals activate BH3-only proteins that can engage both Mcl-1 and Bcl-x(L) (such as Noxa plus Bad), Bak is displaced and induces cell death [10].
• Thus, we propose that there are at least two different pathways of mitochondrial dysfunction; one mediated through Noxa in response to genotoxic stresses and the other through tBid in response to death ligands [15].
• Effective killing of melanoma cells by GSI involved new protein synthesis and a mitochondrial-based pathway mediated by up-regulation of BH3-only members (Bim and NOXA). p53 activation was not necessary for up-regulation of NOXA in melanoma cells [16].
• Noxa RNA interference markedly decreased sensitivity to bortezomib, pointing to this protein as a key mediator between proteasome inhibition and mitochondrial depolarization in MCL cells [17].

Anatomical context of PMAIP1

• Mechanistic analysis of the p53-dependent cell death indicated an apoptotic mechanism involving depolarization of mitochondrial membrane potential, caspase cleavage, and elevated NOXA expression [18].
• Importantly, expression of the 13S isoform of E1A substantially induced the p53 apoptotic target Noxa in several p53-deficient cancer cell lines [19].
• This indicates that Noxa may activate the permeability transition-related pore to release cytochrome c from mitochondria into cytosol [15].
• Interestingly, the Noxa mitochondrial-targeting domain deletion mutant interacted with Bax in a dsRNA-dependent manner and redirected Bax away from the mitochondria, thus acting as a dominant-negative protein [2].
• Noxa induction was confirmed by using reverse transcriptase-PCR and immunoblot analyses in multiple human tumor cell lines [2].

Associations of PMAIP1 with chemical compounds

• Noxa-induced cytochrome c release is inhibited by permeability transition pore inhibitors such as CsA or MgCl2, and Noxa induces an ultra-structural change of mitochondria yielding "swollen" mitochondria that are unlike changes induced by tBid [15].
• The specific role of Noxa became apparent during glucose limitation and involves interaction with the labile Bcl-2 homolog Mcl-1 [20].
• Up-regulation of HIF-1alpha following PMA-induced differentiation was also abolished by addition of Fe(2+) or ascorbate [21].
• Nitric oxide inhibition of homocysteine-induced human endothelial cell apoptosis by down-regulation of p53-dependent Noxa expression through the formation of S-nitrosohomocysteine [22].
• The protein synthesis inhibitor cycloheximide completely abolished the PMA-induced down-modulation of the p53 mRNA, suggesting that a short-lived protein was involved in the down-modulation [23].

Physical interactions of PMAIP1

• By chemical inhibition, site-directed promoter mutagenesis and electrophoretic mobility-shift assay (EMSA), we demonstrated that PMA induced proteins binding to all three Sp1 sites and that they were all required for full induction of MUC5AC promoter activity [24].
• These results suggest that the adhesion functions of CD44 and integrins are differently regulated despite the fact that both are induced by PMA stimulation, and that new protein synthesis is essential for the PMA-induced HA binding by CD44 [25].
• A PMA-induced nuclear factor that bound to the NHE2 promoter was identified as the transcription factor Egr-1 [26].
• Electrophoretic mobility shift assays revealed that tumor necrosis factor or phorbol 12-myristate 13-acetate induced nuclear factor-kappaB binding complexes of Rel A and p50 in E1A and control transfectants, whereas LPS was effective only in E1A transfectants [27].
• These findings suggest that gp120 binding to cellular CD4 receptors induces conformational changes leading to association of the gp120-CD4 complexes with accessory transmembrane molecules that are susceptible to PMA-induced down modulation and can target the virions to clathrin-coated pits [28].

Regulatory relationships of PMAIP1

• Altogether, our results show that Noxa is induced by HIF-1alpha and mediates hypoxic cell death [1].
• The molecular mechanism of Noxa-induced mitochondrial dysfunction in p53-mediated cell death [15].
• Moreover, Bak-oligomerization, which is an essential event for tBid-induced cytochrome c release in the extrinsic death signaling pathway, is not associated with Noxa-induced cytochrome c release [15].
• Reversibly, overexpression of NOXA or PUMA induces apoptosis as evidenced by the activation of BAK and caspase-7 [29].
• Finally, decreasing PLSCR1 expression with small interfering RNA inhibits ATRA/PMA-induced differentiation [30].

Other interactions of PMAIP1

• The 11 cases with 18q gain only showed a consensus region encompassing 18q21.2-18q21.32 and 18q21.33, which contain PMAIP1/MALT1 and BCL2, respectively [31].
• Here we show that two domains (BH3 domain and mitochondrial targeting domain) in Noxa are essential for the release of cytochrome c from mitochondria [15].
• Noxa is a candidate molecule mediating p53-induced apoptosis [1].
• Coexpression of BAD and NOXA killed wild-type but not Bax, Bak doubly deficient cells or Puma deficient cells with Bim knockdown, indicating that activator BH3-only molecules function downstream of inactivator BH3-only molecules to activate BAX-BAK [32].
• When expressed together, BIK and NOXA cause rapid release of mobilized cytochrome c and activation of caspases [33].

Analytical, diagnostic and therapeutic context of PMAIP1

• Among them, Noxa protein expression was investigated with immunohistochemistry in 16 tumors and six corresponding normal mucosa samples [3].
• Notably, we showed that proteasome-mediated down-regulation of Puma and Noxa proteins occurs in 697-Bcl-2 cells after treatment with BSO plus topoisomerase inhibitor, although there is an increase in the protein levels of p53 in these 697-Bcl-2 cells [34].
• Electrophoretic mobility shift assay showed that the PMA-induced activation of the p21WAF1/CIP1 promoter was driven by the specific protein 1 (Sp1) transcription factor through Sp1-binding sites [35].
• Western blotting and confocal microscopy showed that total beta-catenin protein is increased in both cell lines at the time of Noxa induction, with the bulk of the beta-catenin present in the nucleus [36].
• Consequently, harmful DNA damage-dependent signaling events, including NAD depletion, p53 activation, and mitochondrial translocation of PUMA and NOXA, were reduced during post-ischemic reperfusion in hypothermia-treated brains [37].

References