The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.

wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)



Gene Review

PMAIP1  -  phorbol-12-myristate-13-acetate-induced...

Homo sapiens

Synonyms: APR, Immediate-early-response protein APR, NOXA, PMA-induced protein 1, Phorbol-12-myristate-13-acetate-induced protein 1, ...
Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

Disease relevance of PMAIP1


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


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


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


  1. BH3-only protein Noxa is a mediator of hypoxic cell death induced by hypoxia-inducible factor 1alpha. Kim, J.Y., Ahn, H.J., Ryu, J.H., Suk, K., Park, J.H. J. Exp. Med. (2004) [Pubmed]
  2. Involvement of Noxa in cellular apoptotic responses to interferon, double-stranded RNA, and virus infection. Sun, Y., Leaman, D.W. J. Biol. Chem. (2005) [Pubmed]
  3. Noxa in colorectal cancer: a study on DNA, mRNA and protein expression. Jansson, A.K., Emterling, A.M., Arbman, G., Sun, X.F. Oncogene (2003) [Pubmed]
  4. Effect of exercise and food restriction on selected markers of the acute phase response in hamsters. Conn, C.A., Kozak, W.E., Tooten, P.C., Niewold, T.A., Borer, K.T., Kluger, M.J. J. Appl. Physiol. (1995) [Pubmed]
  5. The inflammatory response is an integral part of the stress response: Implications for atherosclerosis, insulin resistance, type II diabetes and metabolic syndrome X. Black, P.H. Brain Behav. Immun. (2003) [Pubmed]
  6. Expression of CD4 controls the susceptibility of THP-1 cells to infection by R5 and X4 HIV type 1 isolates. Konopka, K., Düzgüneş, N. AIDS Res. Hum. Retroviruses (2002) [Pubmed]
  7. Liver tumor development. c-Jun antagonizes the proapoptotic activity of p53. Eferl, R., Ricci, R., Kenner, L., Zenz, R., David, J.P., Rath, M., Wagner, E.F. Cell (2003) [Pubmed]
  8. Chemical inducers of differentiation in Friend leukaemia cells inhibit lymphocyte mitogenesis. Stenzel, K.H., Schwartz, R., Rubin, A.L., Novogrodsky, A. Nature (1980) [Pubmed]
  9. Life in the balance: how BH3-only proteins induce apoptosis. Willis, S.N., Adams, J.M. Curr. Opin. Cell Biol. (2005) [Pubmed]
  10. Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Willis, S.N., Chen, L., Dewson, G., Wei, A., Naik, E., Fletcher, J.I., Adams, J.M., Huang, D.C. Genes Dev. (2005) [Pubmed]
  11. Involvement of BH3-only proapoptotic proteins in mitochondrial-dependent Phenoxodiol-induced apoptosis of human melanoma cells. Yu, F., Watts, R.N., Zhang, X.D., Borrow, J.M., Hersey, P. Anticancer Drugs (2006) [Pubmed]
  12. Enhanced Killing of Melanoma Cells by Simultaneously Targeting Mcl-1 and NOXA. Qin, J.Z., Xin, H., Sitailo, L.A., Denning, M.F., Nickoloff, B.J. Cancer Res. (2006) [Pubmed]
  13. Induction of apoptosis by sphingosine in human leukemic HL-60 cells: a possible endogenous modulator of apoptotic DNA fragmentation occurring during phorbol ester-induced differentiation. Ohta, H., Sweeney, E.A., Masamune, A., Yatomi, Y., Hakomori, S., Igarashi, Y. Cancer Res. (1995) [Pubmed]
  14. BOK and NOXA are essential mediators of p53-dependent apoptosis. Yakovlev, A.G., Di Giovanni, S., Wang, G., Liu, W., Stoica, B., Faden, A.I. J. Biol. Chem. (2004) [Pubmed]
  15. The molecular mechanism of Noxa-induced mitochondrial dysfunction in p53-mediated cell death. Seo, Y.W., Shin, J.N., Ko, K.H., Cha, J.H., Park, J.Y., Lee, B.R., Yun, C.W., Kim, Y.M., Seol, D.W., Kim, D.W., Yin, X.M., Kim, T.H. J. Biol. Chem. (2003) [Pubmed]
  16. p53-independent NOXA induction overcomes apoptotic resistance of malignant melanomas. Qin, J.Z., Stennett, L., Bacon, P., Bodner, B., Hendrix, M.J., Seftor, R.E., Seftor, E.A., Margaryan, N.V., Pollock, P.M., Curtis, A., Trent, J.M., Bennett, F., Miele, L., Nickoloff, B.J. Mol. Cancer Ther. (2004) [Pubmed]
  17. The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and Noxa activation independent of p53 status. Pérez-Galán, P., Roué, G., Villamor, N., Montserrat, E., Campo, E., Colomer, D. Blood (2006) [Pubmed]
  18. An Organometallic Protein Kinase Inhibitor Pharmacologically Activates p53 and Induces Apoptosis in Human Melanoma Cells. Smalley, K.S., Contractor, R., Haass, N.K., Kulp, A.N., Atilla-Gokcumen, G.E., Williams, D.S., Bregman, H., Flaherty, K.T., Soengas, M.S., Meggers, E., Herlyn, M. Cancer Res. (2007) [Pubmed]
  19. E1A activates transcription of p73 and Noxa to induce apoptosis. Flinterman, M., Guelen, L., Ezzati-Nik, S., Killick, R., Melino, G., Tominaga, K., Mymryk, J.S., Gäken, J., Tavassoli, M. J. Biol. Chem. (2005) [Pubmed]
  20. The Noxa/Mcl-1 axis regulates susceptibility to apoptosis under glucose limitation in dividing T cells. Alves, N.L., Derks, I.A., Berk, E., Spijker, R., van Lier, R.A., Eldering, E. Immunity (2006) [Pubmed]
  21. Normoxic stabilization of hypoxia-inducible factor-1alpha by modulation of the labile iron pool in differentiating U937 macrophages: effect of natural resistance-associated macrophage protein 1. Knowles, H.J., Mole, D.R., Ratcliffe, P.J., Harris, A.L. Cancer Res. (2006) [Pubmed]
  22. Nitric oxide inhibition of homocysteine-induced human endothelial cell apoptosis by down-regulation of p53-dependent Noxa expression through the formation of S-nitrosohomocysteine. Lee, S.J., Kim, K.M., Namkoong, S., Kim, C.K., Kang, Y.C., Lee, H., Ha, K.S., Han, J.A., Chung, H.T., Kwon, Y.G., Kim, Y.M. J. Biol. Chem. (2005) [Pubmed]
  23. Tumor-promoting phorbol ester transiently down-modulates the p53 level and blocks the cell cycle. Skouv, J., Jensen, P.O., Forchhammer, J., Larsen, J.K., Lund, L.R. Cell Growth Differ. (1994) [Pubmed]
  24. PMA induces the MUC5AC respiratory mucin in human bronchial epithelial cells, via PKC, EGF/TGF-alpha, Ras/Raf, MEK, ERK and Sp1-dependent mechanisms. Hewson, C.A., Edbrooke, M.R., Johnston, S.L. J. Mol. Biol. (2004) [Pubmed]
  25. Inducible binding of human lymphocytes to hyaluronate via CD44 does not require cytoskeleton association but does require new protein synthesis. Murakami, S., Shimabukuro, Y., Miki, Y., Saho, T., Hino, E., Kasai, D., Nozaki, T., Kusumoto, Y., Okada, H. J. Immunol. (1994) [Pubmed]
  26. Zinc finger transcription factor Egr-1 is involved in stimulation of NHE2 gene expression by phorbol 12-myristate 13-acetate. Malakooti, J., Sandoval, R., Memark, V.C., Dudeja, P.K., Ramaswamy, K. Am. J. Physiol. Gastrointest. Liver Physiol. (2005) [Pubmed]
  27. Endotoxin-specific NF-kappaB activation in pulmonary epithelial cells harboring adenovirus E1A. Keicho, N., Higashimoto, Y., Bondy, G.P., Elliott, W.M., Hogg, J.C., Hayashi, S. Am. J. Physiol. (1999) [Pubmed]
  28. Phorbol ester-induced down modulation of tailless CD4 receptors requires prior binding of gp120 and suggests a role for accessory molecules. Golding, H., Dimitrov, D.S., Manischewitz, J., Broder, C.C., Robinson, J., Fabian, S., Littman, D.R., Lapham, C.K. J. Virol. (1995) [Pubmed]
  29. Endoplasmic reticulum stress-induced apoptosis: multiple pathways and activation of p53-up-regulated modulator of apoptosis (PUMA) and NOXA by p53. Li, J., Lee, B., Lee, A.S. J. Biol. Chem. (2006) [Pubmed]
  30. Protein kinase Cdelta mediates retinoic acid and phorbol myristate acetate-induced phospholipid scramblase 1 gene expression: its role in leukemic cell differentiation. Zhao, K.W., Li, X., Zhao, Q., Huang, Y., Li, D., Peng, Z.G., Shen, W.Z., Zhao, J., Zhou, Q., Chen, Z., Sims, P.J., Wiedmer, T., Chen, G.Q. Blood (2004) [Pubmed]
  31. Translocation t(14;18) and gain of chromosome 18/BCL2: effects on BCL2 expression and apoptosis in B-cell non-Hodgkin's lymphomas. Galteland, E., Sivertsen, E.A., Svendsrud, D.H., Smedshammer, L., Kresse, S.H., Meza-Zepeda, L.A., Myklebost, O., Suo, Z., Mu, D., Deangelis, P.M., Stokke, T. Leukemia (2005) [Pubmed]
  32. Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies. Kim, H., Rafiuddin-Shah, M., Tu, H.C., Jeffers, J.R., Zambetti, G.P., Hsieh, J.J., Cheng, E.H. Nat. Cell Biol. (2006) [Pubmed]
  33. Endoplasmic reticulum BIK initiates DRP1-regulated remodelling of mitochondrial cristae during apoptosis. Germain, M., Mathai, J.P., McBride, H.M., Shore, G.C. EMBO J. (2005) [Pubmed]
  34. Inhibition of glutathione synthesis overcomes Bcl-2-mediated topoisomerase inhibitor resistance and induces nonapoptotic cell death via mitochondrial-independent pathway. Yoshida, A., Takemura, H., Inoue, H., Miyashita, T., Ueda, T. Cancer Res. (2006) [Pubmed]
  35. Signal transduction of phorbol 12-myristate 13-acetate (PMA)-induced growth inhibition of human monocytic leukemia THP-1 cells is reactive oxygen dependent. Traore, K., Trush, M.A., George, M., Spannhake, E.W., Anderson, W., Asseffa, A. Leuk. Res. (2005) [Pubmed]
  36. MG132 induced apoptosis is associated with p53-independent induction of pro-apoptotic Noxa and transcriptional activity of beta-catenin. Jüllig, M., Zhang, W.V., Ferreira, A., Stott, N.S. Apoptosis (2006) [Pubmed]
  37. Mild hypothermia diminishes oxidative DNA damage and pro-death signaling events after cerebral ischemia: a mechanism for neuroprotection. Ji, X., Luo, Y., Ling, F., Stetler, R.A., Lan, J., Cao, G., Chen, J. Front. Biosci. (2007) [Pubmed]
WikiGenes - Universities