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Puma, a critical mediator of cell death — one decade on from its discovery

Abstract

PUMA (p53 upregulated modulator of apoptosis) is a pro-apoptotic member of the BH3-only subgroup of the Bcl-2 family. It is a key mediator of p53-dependent and p53-independent apoptosis and was identified 10 years ago. The PUMA gene is mapped to the long arm of chromosome 19, a region that is frequently deleted in a large number of human cancers. PUMA mediates apoptosis thanks to its ability to directly bind known anti-apoptotic members of the Bcl-2 family. It mainly localizes to the mitochondria. The binding of PUMA to the inhibitory members of the Bcl-2 family (Bcl-2-like proteins) via its BH3 domain seems to be a critical regulatory step in the induction of apoptosis. It results in the displacement of the proteins Bax and/or Bak. This is followed by their activation and the formation of pore-like structures on the mitochondrial membrane, which permeabilizes the outer mitochondrial membrane, leading to mitochondrial dysfunction and caspase activation. PUMA is involved in a large number of physiological and pathological processes, including the immune response, cancer, neurodegenerative diseases and bacterial and viral infections.

Abbreviations

ADI/II:

activation domain I/II

Apaf-1:

apoptosis protease activating factor-1

Bad:

Bcl-2 associated death promoter

Bak:

Bcl-2 antagonist killer

Bax:

Bcl-2 associated protein x

Bcl-2:

B-cell leukemia/lymphoma-2

BH1-4:

Bcl-2 homology domains 1-4

Bid:

BH3 interacting domain death agonist

Bik:

Bcl-2 interacting killer

Bim:

Bcl-2 interacting mediator of cell death

Bmf:

Bcl-2 modifying factor

Bod:

Bcl-2-related ovarian death gene

Bok:

Bcl-2 ovarian killer

BS1/2:

p53 binding site 1/2

CHOP:

C/EBP homologous protein

DEN:

diethylnitrosamine

GSK-3:

glycogen synthase kinase-3

HRK:

harakiri, activator of apoptosis

HSPCs:

hematopoietic stem/progenitor cells

HSV-1:

human herpes virus

IKK:

IκB kinase

IL-3:

interleukin 3

Lys:

lysine

Mcl-1:

myeloid cell leukemia-1

MEFs:

mouse embryo fibroblasts

miRNA/miR:

microRNA

MLS:

mitochondrial localization signal

MOMP:

mitochondrial outer membrane permeabilization

NOXA (PMAP1):

phorbol-12-myristate-13-acetate-induced protein 1

OMM:

outer mitochondrial membrane

PCD:

programmed cell death

PI3K:

phosphoinositide 3-kinase

PUMA:

p53 upregulated modulator of apoptosis

ROS:

reactive oxygen species

Ser:

serine

Smac/DIABLO:

second mitochondria-derived activator or caspases/direct IAP binding protein with low pI

TRB3:

tribbles 3 homolog

UV-γIR:

ultraviolet-gamma irradiation

References

  1. Green, D.R. and Reed, J.C. Mitochondria and apoptosis. Science 281 (1998) 1309–1312.

    PubMed  CAS  Article  Google Scholar 

  2. Zhivotovsky, B. and Orrenius, S. Cell cycle and cell death in disease: past, present and future. J. Intern. Med. 268 (2010) 395–409.

    PubMed  CAS  Article  Google Scholar 

  3. Caroppi, P., Sinibaldi, F., Fiorucci, L. and Santucci, R. Apoptosis and human diseases: mitochondrion damage and lethal role of released cytochrome c as proapoptotic protein. Curr. Med. Chem. 16 (2009) 4058–4065.

    PubMed  CAS  Article  Google Scholar 

  4. Plati, J. and Khosravi-Far, R. Apoptotic cell signaling in cancer progression and therapy. Integr. Biol. 3 (2011) 279–296.

    CAS  Article  Google Scholar 

  5. Evan, G. and Vousden, K.M. Proliferation, cell cycle and apoptosis in cancer. Nature 111 (2001) 342–348.

    Article  Google Scholar 

  6. Green, D.R. Apoptotic pathway: paper wraps stone blunts scissors. Cell 102 (2000) 1–4.

    PubMed  CAS  Article  Google Scholar 

  7. Hengartner, M.O. The biochemistry of apoptosis. Nature 407 (2000) 770–776.

    PubMed  CAS  Article  Google Scholar 

  8. Green, D.R. and Evan, G.J. A matter of life and death. Cancer Cell 1 (2002) 19–30.

    PubMed  CAS  Article  Google Scholar 

  9. Mohamed, N., Gutierrez, A., Nunez, M., Cocca, C., Marit, G., Cricco, G., Medina, V., Rivera, E. and Bergoc, R. Mitochondrial apoptotic pathways. Biocell 29 (2005) 149–161.

    Google Scholar 

  10. van Gurp, M., Festjens, N., van Loo, G., Saelens, X. and Vandenabeele, P. Mitochondrial intermembrane proteins in cell death. Biochem. Biophys. Res. Commun. 304 (2003) 487–497.

    PubMed  Article  CAS  Google Scholar 

  11. Cain, K., Bratton, S.B., Langlais, C., Walker, G., Brown, D.G., Sun, X.M. and Cohen, G.M. Apaf-1 oligomerizes into biologically active approximately 700-kDa and inactive approximately 1.4 MDa apoptosome complex. J. Biol. Chem. 275 (2000) 6067–6070.

    PubMed  CAS  Article  Google Scholar 

  12. Hill, M.M., Adrian, C. and Martin, S.J. Portrait of a killer: the mitochondrial apoptosome emerges from the shadows. Mol. Interv. 3 (2003) 19–26.

    PubMed  CAS  Article  Google Scholar 

  13. Riedl, S.J. and Salvesen, G.S. The apoptosome: signaling platform of cell death. Nat. Rev. Mol. Cell. Biol. 8 (2007) 405–413.

    PubMed  CAS  Article  Google Scholar 

  14. Borner, C. The Bcl-2 protein family: sensors and checkpoints for life-ordeath decisions. Mol. Immunol. 39 (2003) 615–647.

    PubMed  CAS  Article  Google Scholar 

  15. Adams, J.M. and Cory, S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 26 (2007) 1324–1337.

    PubMed  CAS  Article  Google Scholar 

  16. Lanave, C., Santamaria, M. and Saccone, C. Comparative genomics: the evolutionary history of the Bcl-2 family. Gene 333 (2004) 71–79.

    PubMed  CAS  Article  Google Scholar 

  17. Willis, S.N. and Adams, J.M. Life in the balance: how BH3-only proteins induce apoptosis. Curr. Opin. Cell Biol. 17 (2005) 617–625.

    PubMed  CAS  Article  Google Scholar 

  18. Lomonosova, E. and Chinnadurai, G. BH3-only proteins in apoptosis and beyond: an overview. Oncogene 27 (2008) 2–19.

    Article  CAS  Google Scholar 

  19. Letai, A., Bassik, M.C., Walensky, L.D., Sorcinelli, M.D., Weiler, S. and Korsmeyer, S.J. Distinct BH3 domains either sensitize or acrivate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2 (2002) 183–192.

    PubMed  CAS  Article  Google Scholar 

  20. Chipuk, J.E., Moldoveanu, T., Llambi, F., Parsons, M.J. and Green, D.R. The BCL-2 family reunion. Mol. Cell 37 (2010) 299–310.

    PubMed  CAS  Article  Google Scholar 

  21. Elkholi, R., Floros, K.V. and Chipuk, J.E. The role of BH3-only proteins in tumor cell development, signaling and treatment. Genes Cancer 2 (2011) 523–537.

    PubMed  CAS  Article  Google Scholar 

  22. Fricker, M., O’Prey, J., Tolkovsy, A.M and Ryan, K.M. Phosphorylation of Puma modulates its apoptotic function by regulating protein stability. Cell Death Dis. 1 (2010) DOI: e59; doc: 10.1038/cddis.2010.38.

  23. Jeffers, J.R., Parganas, E., Lee, Y., Yang, C., Wang, J., Brennan, J., MacLean, K.H., Han, J., Chittenden, T., Ihle, J.N., McKinnon, P.J., Cleveland, J.L. and Zambetti, G.P. Puma is an essential mediator of p53-dependent and -independent apoptotic pathways. Cancer Cell 4 (2003) 321–328.

    PubMed  CAS  Article  Google Scholar 

  24. Yu, J. and Zhang, L. PUMA, a potent killer with or without p53. Oncogene 27 (2008) S71–S83.

    PubMed  CAS  Article  Google Scholar 

  25. Yu, J., Zhang, L., Hwang, P.M., Kinzler, K.W. and Vogelstein, B. PUMA induces the rapid apoptosis of colorectal cancer cells. Mol. Cell. 7 (2001) 673–682.

    PubMed  CAS  Article  Google Scholar 

  26. Nakano, K. and Vousden, K.H. PUMA, a novel proapoptotic gene, is induced by p53. Mol. Cell. 7 (2001) 683–694.

    PubMed  CAS  Article  Google Scholar 

  27. Han, J., Flemington, C., Houghton, A.B., Gu, Z., Zambetti, G.P., Lutz, R.J., Zhu, L. and Chittenden, T. Expression of bbc3, a pro-apoptotic BH3-only gene, is regulated by diverse cell death and survival signals. Proc. Natl. Acad. Sci. USA 98 (2001) 11318–11323.

    PubMed  CAS  Article  Google Scholar 

  28. Yu, J., Wang, Z., Kinzler, K.W., Vogelstein, B. and Zhang, L. PUMA mediates the apoptotic response to p53 in colorectal cancer cells. Proc. Natl. Acad. Sci. USA 100 (2003) 1931–1936.

    PubMed  CAS  Article  Google Scholar 

  29. Yee, K.S. and Vousden, K.H. Contribution of membrane localization to the apoptotic activity of PUMA. Apoptosis 13 (2008) 87–95.

    PubMed  Article  Google Scholar 

  30. Day, C.L., Smits, C., Fan, C.F., Lee, E.F., Fairlie, W.D. and Hinds, M.G. Structure of the BH3 domains from the p53-inducible BH3-only proteins Noxa and Puma in complex with Mcl-1. J. Mol. Biol. 380 (2008) 958–971.

    PubMed  CAS  Article  Google Scholar 

  31. Cregan, S.P., Arbour, N.A., Maclaurin, J.G., Callaghan, S.M., Fortin, A., Cheung, E.C., Guberman, D.S., Park, D.S. and Slack, R.S. p53 activation domain 1 is essential for PUMA upregulation and p53-mediated neuronal cell death. J. Neurosci. 24 (2004) 10003–10012.

    PubMed  CAS  Article  Google Scholar 

  32. Wang, X., Wang, J., Lin, S., Geng, J., Wang, J. and Jiang., B. Sp1 is involved in H2O2-induced PUMA gene expression and apoptosis in colorectal cancer cells. J. Exp. Clin. Cancer Res. 24 (2008) 27–44.

    Google Scholar 

  33. Ming, L., Wang, P., Bank, A., Yu, J. and Zhang, L. PUMA dissociated Bax and Bcl-XL to induce apoptosis in colon cancer cells. J. Bioch. Chem. 28 (2006) 16034–16042.

    Article  Google Scholar 

  34. Chipuk, J.E, Bouchier-Hayes, L., Kuwana, T., Newmayer, D.D. and Green, D.R. PUMA couples the nucler and cytoplasmic proapoptotic function of p53. Science 309 (2005) 1732–1735.

    PubMed  CAS  Article  Google Scholar 

  35. Zhang, C., Junxia, Z., Zhang, A., Wang, Y., Han, L., You, Y., Pu, P. and Kang, C. PUMA is a novel target of miR-221/222 in human epithelial cancers. Int. J. Oncol. 37 (2010) 1621–1626.

    PubMed  CAS  Article  Google Scholar 

  36. Zhang, C., Zhang, J., Zhang, A., Shi, Z., Han, L., Jia, Z., Yang, W., Wang, G., Jiang, T., You, Y., Pu, P., Cheng, J. and Kang, C. MiR-221 and miR-222 target PUMA to induce cell survival in glioblastoma. Mol. Cancer 9 (2010) 1–9.

    Google Scholar 

  37. Jabbour, A.M., Daunt, C.P., Green, B.D., Vogel, S., Gordon, L., Lee, R.S., Silke, N., Pearson, R.B., Vandenberg, C.J., Kelly, P.N., Nutt, S.L., Strasser, A., Borner, C. and Ekert, P.G. Myeloid progenitor cells lacking p53 exhibit delayed up-regulation of Puma and prolonged survival after cytokine deprivation. Blood 115 (2010) 344–352.

    PubMed  CAS  Article  Google Scholar 

  38. Ming, L., Sakaida, T., Yue, W., Jha, A., Zhang L. and Yu J. Sp1 and p73 activate PUMA following serum starvation. Carcinogenesis 29 (2008) 1878–1884.

    PubMed  CAS  Article  Google Scholar 

  39. Ray, R.M., Bhattacharya, S. and Johnson, L.R. Mdm2 inhibition induces apoptosis in p53 deficient human colon cancer cells by activating p73- and E2F1-mediated expression of PUMA and Siva-1. Apoptosis 16 (2011) 35–44.

    PubMed  CAS  Article  Google Scholar 

  40. You, H., Pellegrini, M., Tsuchihara, K., Yamamoto, K., Häcker, G., Erlacher, M., Villunger, A. and Mak T.W. FOXO3a-dependent regulation of Puma in response to cytokine/growth factor withdrawal. J. Exp. Med. 203 (2006) 1657–1663.

    PubMed  CAS  Article  Google Scholar 

  41. Dudgeon, C., Wang, P., Sun, X., Peng, R., Sun, Q., Yu, J. and Zhang, L. PUMA induction by FoxO3a mediates the anticancer activities of the broadrange kinase inhibitor UCN-01. Mol. Cancer Ther. 9 (2010) 2893–2902.

    PubMed  CAS  Article  Google Scholar 

  42. Hershko, T. and Ginsberg, D. Up-regulation of Bcl-2 homology 3 (BH3)-only proteins by E2F1 mediates apoptosis. J. Biol. Chem. 279 (2004) 8627–8634.

    PubMed  CAS  Article  Google Scholar 

  43. Wu, B., Qiu, W., Wang, P., Yu, H., Cheng, T., Zambetti, G.P., Zhang, L. and Yu J. p53 independent induction of PUMA mediates intestinal apoptosis in response to ischaemia-reperfusion. Gut 56 (2007) 645–654.

    PubMed  CAS  Article  Google Scholar 

  44. Li, J., Lee, B. and Lee A.S. Endoplasmic reticulum stress-induced apoptosis: multiple pathways and activation of p53-up-regulated modulator of apoptosis (PUMA) and NOXA by p53. J. Biol. Chem. 281 (2006) 7260–7270.

    PubMed  CAS  Article  Google Scholar 

  45. Nickson, P., Toth, A. and Erhardt, P. PUMA is critical for neonatal cardiomyocyte apoptosis induced by endoplasmic reticulum stress. Cardiovasc. Res. 73 (2007) 48–56.

    PubMed  CAS  Article  Google Scholar 

  46. Webster, K.A. Puma joins the battery of BH3-only proteins that promote death and infarction during myocardial ischemia. Am. J. of Physiol. Heart Circ. Physiol. 291 (2006) 20–22.

    Article  CAS  Google Scholar 

  47. Toth, A., Jeffers, J.R., Nickson, P., Min, J-Y., Morgan, J.P., Zambetti, G.P. and Erhardt, P. Targeted deletion of Puma attenuates cardiomyocyte death and improves cardiac function during ischemia-reperfusion. Am. J. Physiol. Heart Circ. Physiol. 291 (2006) 52–60.

    Article  CAS  Google Scholar 

  48. Cazanave, S.C., Elmi, N.A., Akazawa, Y., Bronk, S.F., Mott, J.L. and Gores, G.J. CHOP and AP-1 cooperatively mediate PUMA expression during lipoapoptosis. Am. J. Physiol. Gastrointest. Liver Physiol. 299 (2010) 236–243.

    Article  CAS  Google Scholar 

  49. Fernandez, P.C., Frank, S.R., Wang, L., Schroeder, M., Liu, S, Greene, J., Cocito, A. and Amati B. Genomic targets of the human c-Myc protein. Genes Dev. 17 (2003) 1115–1129.

    PubMed  CAS  Article  Google Scholar 

  50. Garrison, S.P., Jeffers, J.R., Yang, C., Nilsson, J.A., Hall, M.A., Rehg, J.E., Yue, W., Yu, J., Zhang, L., Onciu, M., Sample, J.T., Cleveland, J.L. and Zambetti, G.P. Selection against PUMA gene expression in Myc-driven Bcell lymphomagenesis. Mol. Cell. Biol. 28 (2008) 5391–5402.

    PubMed  CAS  Article  Google Scholar 

  51. Happo, L., Strasser, A. and Scott, C.L. BH3-only Proteins. in: Cell Death (Melino, G. and Vaux, D., Ed.), 1th edition, John Wiley&Sons — Ltd, 2010, 75–90.

  52. Erlacher, M., Michalak, E.M., Strasser, A. and Villunger, A. The BH3-only proteins Puma and Noxa: Two Brothers in Arms. in: Apoptosis and Cancer Therapy: From Cutting-edge Science to Novel Therapeutic Concepts, (Debatin, K.M. and Fulda, S., Ed.), Wiley-VCH Verlag GmbH, Weinheim, Germany. DOI: 10.1002/9783527619665.ch13, 2008, 379–402.

    Google Scholar 

  53. Lozano, G. and Zambetti, G.P. What have animals models taught us about the p53 pathway? J. Pathol. 205 (2005) 206–220.

    PubMed  CAS  Article  Google Scholar 

  54. Zapaśnik, M. and Cymerys, J.M. p53 protein — guardian of the genome in the viral infection. Post. Biol. Kom. 36 (2009) 565–582.

    Google Scholar 

  55. Michalak, E.M., Villunger, A., Adams, J.M. and Strasser, A. In several cell types tumour suppressor p53 induces apoptosis largely via Puma but Noxa can contribute. Cell Death Differ. 15 (2008) 1019–1029.

    PubMed  CAS  Article  Google Scholar 

  56. Qiu, W., Carson-Walter, E.B., Liu, H., Epperly, M., Greenberger, J.S., Zambetti, G.P., Zhang, L., Yu, J. PUMA regulates intestinal progenitor cell radiosensitivity and gastrointestinal syndrome. Cell Stem Cell 2 (2008) 576–583.

    PubMed  CAS  Article  Google Scholar 

  57. Wang, P., Yu, J. and Zhang, L. The nuclear function of p53 is required for PUMA-mediated apoptosis induced by DNA damage. Proc. Natl. Acad. Sci. USA 104 (2007) 4054–4059.

    PubMed  CAS  Article  Google Scholar 

  58. Charvet, C., Wissler, M., Brauns-Schubert, P., Wang, S-J., Tang, Y., Sigloch, F.C., Mellert, H., Brandenburg, M., Lindner, S.E., Breit, B., Green, D.R., McMahon, S.B., Borner, C., Gu, W. and Maurer U. Phosphporylation of Tip60 by GSK-3 determines the induction of PUMA and apoptosis by p53. Mol. Cell. 42 (2011) 584–596.

    PubMed  CAS  Article  Google Scholar 

  59. Tang, Y., Luo, J., Zhang, W. and Gu, W. Tip60-dependent acetylation of p53modulates the decision between cell-cycle arrest and apoptosis. Mol. Cell 24 (2006) 827–839.

    PubMed  CAS  Article  Google Scholar 

  60. Sykes, S.M., Mellert, H.S., Holbert, M.A., Li, K., Marmorstein, R., Lane, W.S. and McMahon, S.B. Acetylation of the p53 DNA binding domain regulates apoptosis induction. Mol. Cell 24 (2006) 841–851.

    PubMed  CAS  Article  Google Scholar 

  61. Ibrahim, S.H., Akazawa, Y., Cazanave, S.C., Bronk, S.F., Elmi, N.A., Werneburg, N.W., Billadeau, D.D. and Gores, G.J. Glycogen synthase kinase-3 (GSK-3) inhibition attenuates hepatocyte lipoapoptosis. J. Hepatol. 54 (2011) 765–772.

    PubMed  CAS  Article  Google Scholar 

  62. Hetz, C. and Glimcher, L. The daily job of night killers: alternative roles of the BCL-2 family in organelle physiology. Trends Cell Biol. 18 (2007) 38–44.

    Article  CAS  Google Scholar 

  63. Luo, X., He, Q., Huang, Y. and Sheikh, M.S. Transcriptional upregulation of PUMA modulates endoplasmic reticulum calcium pool depletioninduced apoptosis via Bax activation. Cell Death Differ. 12 (2005) 1310–1318.

    PubMed  CAS  Article  Google Scholar 

  64. Jiang, C.C., Lucas, K., Avery-Kiejda, K.A., Wade, M., deBock, C.E., Thorne, R.F., Allen, J., Hersey, P. and Zhang, X.D. Up-regulation of Mcl-1 is critical for survival of human melanoma cells upon endoplasmic reticulum stress. Cancer Res. 68 (2008) 6708–6717.

    PubMed  CAS  Article  Google Scholar 

  65. Wei, J., O’Brien, D., Vilgelm, A., Piazuelo, M.B., Correa, P., Washinghton, M.K., El-Rifai, W., Peek, R.M. and Zaika A. Interaction of Helicobacter pylori with gastric epithelial cells is mediated by the p53 protein family. Gastroenterology 134 (2008) 1412–1423.

    PubMed  CAS  Article  Google Scholar 

  66. Perfettini, J-L., Roumier, T., Casted, M., Larochette, N., Boya, P., Raynal, B., Lazar, V., Ciccosanti, F., Nardacci, R., Penninger, J., Piacentini, M. and Kroemer, G. NF-κB and p53 qre the dominant apoptosis-inducing transcription factors elicited by the HIV-1 envelope. J. Exp. Med. 199 (2004) 629–640.

    PubMed  CAS  Article  Google Scholar 

  67. Rodrigues, R., Paranhos-Baccala, G., Vernet, G. and Peyrefitte, C.N. Crimean-congo hemorrhagic fever virus-infected hepatocytes induced ERstress and apoptosis crosstalk. PLoS 7 (2012) 1–11.

    Google Scholar 

  68. Bauer, A., Villunger, A., Labi, V., Fischer, S.F., Strasser, A., Wagner, H., Schmid, R.M. and Häcker, G. The NF-κB regulator Bcl-3 and the BH3-only proteins Bim and Puma control the death of activated T cells. Proc. Natl. Acad. Sci. USA 103 (2006) 10979–10984.

    PubMed  CAS  Article  Google Scholar 

  69. Fisher, S.F., Belz, G.T. and Strasser, A. BH3-only protein Puma contributes to death of antigen-specific T cells during shutdown of an immune response to acute viral infection. Proc. Natl. Acad. Sci. USA 105 (2008) 3035–3040.

    Article  Google Scholar 

  70. Häcker, G., Bauer, A. and Villunger, A. Apoptosis in activated T cells: what are the triggers, and what the signal transducers? Cell Cycle 5 (2006) 2421–2424.

    PubMed  Article  Google Scholar 

  71. Hildeman, D., Jorgensen, T., Kappler, J. and Marrack P. Apoptosis and the homeostatic control of immune responses. Curr. Opin. Immunol. 19 (2007) 516–521.

    PubMed  CAS  Article  Google Scholar 

  72. Steckley, D., Karajgikar, M., Dale, L.B., Fuerth, B., Swan, P., Drummond-Main, C., Poulter, M.O., Ferguson, S.S., Strasser, A. and Cregan, S.P. Puma is a dominant regulator of oxidative stress induced Bax activation and neuronal apoptosis. J. Neurosci. 27 (2007) 12989–12999.

    PubMed  CAS  Article  Google Scholar 

  73. Sandow, J.J. Regulation of the BH3-only protein PUMA by growth factor signalling. Ph.D. Thesis of the University of Adelaide, School of Medicine, 2011, 1–144.

  74. Dewson, G. and Kluck, R.M. Mechanisms by which Bak and Bax permeabilise mitochondria during apoptosis. J. Cell Sci. 122 (2009) 2801–2808.

    PubMed  CAS  Article  Google Scholar 

  75. Häcker, G. and Weber A. BH3-only proteins trigger cytochrome c release, but how? Arch. Biochem. Biophys. 462 (2007) 150–155.

    PubMed  Article  CAS  Google Scholar 

  76. Kim, H., Tu, H.C., Ren, D., Takeuchi, O., Jeffers, J.R., Zambetti, G.P., Hsieh, J.J. and Cheng, E.H. Stepwise activation of BAX and BAK by tBID, BIM, and PUMA initiates mitochondrial apoptosis. Mol. Cell 36 (2009) 487–499.

    PubMed  CAS  Article  Google Scholar 

  77. Gallenne, T., Gautier, F., Oliver, L., Hervouet, E., Noël, B., Hickman, J.A., Geneste, O., Cartron, P.F., Vallette, F.M., Manon, S. and Juin, P. Bax activation by the BH3-only protein Puma promotes cell dependence on antiapoptotic Bcl-2 family members. J. Cell Biol. 185 (2009) 279–290.

    PubMed  CAS  Article  Google Scholar 

  78. Kuwana, T., Bouchier-Hayes, L., Chipuk, J.E., Bonzon, C., Sullivan, B.A., Green, D.R., and Newmeyer, D.D. BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol. Cell 17 (2005) 525–535.

    PubMed  CAS  Article  Google Scholar 

  79. Westphalm D., Dewson, G., Czabotar, P.E. and Kluck, R.M. Molecular biology of Bax and Bak activation and action. Biochim. Biophys. Acta 1813 (2011) 521–531.

    Article  CAS  Google Scholar 

  80. Lindsay, J., Esposti, M.D. and Gilmore, A.P. Bcl-2 proteins and mitochondria-specificity in membrane targeting for death. Biochim. Biophys. Acta 1813 (2011) 532–539.

    PubMed  CAS  Article  Google Scholar 

  81. Ghiotto, F., Fais, F. and Bruno, S. BH3-Only Proteins: The death puppeteer’s wires. Cytometry A 77 (2010) 11–21.

    PubMed  Google Scholar 

  82. Giam, M., Huang, D.S.C. and Bouillet, P. BH3-only proteins and their roles in programmed cell death. Oncogene 27 (2009) 128–136.

    Article  CAS  Google Scholar 

  83. Shamas-Din, A., Brahmbhatt, H., Leber, B. and Andrews, D.W. BH3-only proteins: orchestrators of apoptosis. Biochim. Biophys. Acta 1813 (2010) 508–520.

    PubMed  Article  CAS  Google Scholar 

  84. Leber, B., Lin, J. and Andrews, D. W. Embedded Together: the life and death consequences of interaction of the Bcl-2 family with membranes. Apoptosis 12 (2007) 897–911.

    PubMed  CAS  Article  Google Scholar 

  85. Chipuk, J.E. and Green, D.R. How do BCL-2 proteins induce mitochondria outer membrane permeabilization? Trends Cell Biol. 18 (2008) 157–164.

    PubMed  CAS  Article  Google Scholar 

  86. Shore, G.C. Apoptosis: it’s BAK to VDAC. EMBO Rep. 10 (2009) 1311–1313.

    PubMed  CAS  Article  Google Scholar 

  87. Gavathiotis, E., Suzuki, M., Davis, M.L., Pitter, K., Bird, G.H., Katz, S.G., Tu, H.C., Kim, H., Cheng, E.H., Tjandra, N. and Walensky, L.D. BAX activation is initiated at a novel interaction site. Nature 455 (2008) 1076–81.

    PubMed  CAS  Article  Google Scholar 

  88. Willis, S.N., Fletcher, J.I., Kaumann, T., van Delft, M.F., Chen, L., Czabotar, P.E., Lerino, H., Lee, E.F., Fairlie, W.D., Bouillet, P., Strasser, A., Kluck, R.M., Adams, J.M. and Huang, D.C.S. Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science 315 (2007) 856–859.

    PubMed  CAS  Article  Google Scholar 

  89. Jabbour, A.M., Heraud, J.E., Daunt, C.P., Kaufmann, T., Sandow, J., O’Reilly, L.A., Callus, B.A., Lopez, A., Strasser, A., Vaux, D.L. and Ekert, P.G. Puma indirectly activates Bax to cause apoptosis in the absence of Bid or Bim. Cell Death Differ. 16 (2009) 555–563.

    PubMed  CAS  Article  Google Scholar 

  90. Chipuk, J.E., Fisher, J.C., Dillon, C.P., Kriwacki, R.W., Kuwana, T. and Green, D.R. Mechanism of apoptosis induction by inhibition of the antiapoptotic BCL-2 proteins. Proc. Natl. Acad. Sci. USA. 105 (2008) 20327–20332.

    PubMed  CAS  Article  Google Scholar 

  91. Chen, L., Willis, S.N., Wei, A., Smith, B.J., Fletcher, J.I., Hinds, M.G., Colman, P.M., Day, C.L., Adams, J.M. and Huang, D.C. Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol. Cell 17 (2005) 393–403.

    PubMed  CAS  Article  Google Scholar 

  92. Vaseva, A.V. and Moll, U.M. The mitochondrial p53 pathway. Biochim. Biophys. Acta 1787 (2009) 414–420.

    PubMed  CAS  Article  Google Scholar 

  93. Vousden, K.H. Apoptosis - p53 and PUMA: a deadly duo. Science 309 (2005) 1685–1686.

    PubMed  CAS  Article  Google Scholar 

  94. Chipuk, J.E., Bouchier-Haues, L., Kuwana, T., Newmeyer, D.D. and Green D.R. PUMA couples the nuclear and cytoplasmic proapoptotic function of p53. Science 309 (2005) 1732–1735.

    PubMed  CAS  Article  Google Scholar 

  95. Wolff, S., Erster, S., Palacios, G. and Moll, U.M. p53’s mitochondrial translocation and MOMP action is independent of Puma and Bax and severaly disrupts mitochondrial membrane integrity. Cell Res. 18 (2008) 733–744.

    PubMed  CAS  Article  Google Scholar 

  96. Yoo, N.J., Lee, J.W., Jeong, E.G. and Lee, S.H. Immunohistochemical analysis of pro-apoptotic PUMA protein and mutational analysis of PUMA gene in gastric carcinomas. Dig. Liver Dis. 39 (2007) 222–227.

    PubMed  CAS  Article  Google Scholar 

  97. Kuroda J. and Taniwaki, M. Involvement of BH3-only proteins in hematologic malignancies. Crit. Rev. Oncol. Hematol. 71 (2009) 89–101.

    PubMed  Article  Google Scholar 

  98. Pietsch, E.C., Sykes, S.M., McMahon, S.B. and Murphy, M.E. The p53 family and programmed cell death. Oncogene 27 (2008) 6507–6521.

    PubMed  CAS  Article  Google Scholar 

  99. Hoque, M.O., Begum, S., Sommer, M., Lee, T., Trink, B., Ratovitski, E. and Sidransky, D. PUMA in head and neck cancer. Cancer Lett. 199 (2003) 75–81.

    PubMed  Article  CAS  Google Scholar 

  100. Ahn, C.H., Jeong, E.G., Kim, S.S., Lee, J.W., Lee, S.H., Kim, S.H., Kim, M.S., Yoo, N.J. and Lee, S.H. Expressional and mutational analysis of proapoptotic Bcl-2 member PUMA in hepatocellular carcinomas. Dig. Dis. Sci. 53 (2008) 1395–1399.

    PubMed  CAS  Article  Google Scholar 

  101. Kim, M.R, Jeong, E.G., Chae, B., Lee, J.W., Soung, Y.H., Nam, S.W., Lee, J.Y., Yoo, N.J. and Sug H Lee. Pro-apoptotic PUMA and antiapoptotic phospho-BAD are highly expressed in colorectal carcinomas. Dig. Dis. Sci. 52 (2007) 2751–2756.

    PubMed  CAS  Article  Google Scholar 

  102. Michalak, E.M., Jansen, E.S., Happo, L., Cragg, M.S., Tai, L., Smyth, G.K., Strasser, A., Adams, J.M. and Scott, C.L. Puma and to a lesser extent Noxa are suppressors of Myc-induced lymphomagenesis. Cell Death Differ. 16 (2009).

  103. Sharma, A.D., Narain, N., Händel, E-M., Iken, M., Singhal, N., Cathomen, T., Manns, M.P., Schöler, H.R., Ott, M. and Cantz, T. MicroRNA-221 regulates FAS-induced fulminant liver failure. Hepatology 53 (2011) 1651–1661.

    PubMed  CAS  Article  Google Scholar 

  104. Shao, L., Sun, Y., Zhang, Z., Feng, W., Gao, Y., Cai, Z., Wang, Z.Z., Look, A.T. and Wu, W.S. Deletion of proapototic Puma selectively protects hematopoietic stem and progenitor cells against high dose radiation. Blood 115 (2010) 4707–4714.

    PubMed  CAS  Article  Google Scholar 

  105. Yu, H., Shen, H., Yuan, Y., Xu-Feng, R., Hu, X., Garrison, S.P., Zhang, L., Yu, J., Zambetti, G.P. and Cheng, T. Deletion of Puma protects hematopoietic stem cells and confers long term survival in response to high-dose radiation. Blood 115 (2010) 3472–3480.

    PubMed  CAS  Article  Google Scholar 

  106. Labi, V., Erlacher, M., Krumschnabel, G., Manzl, C., Tzankov, A., Pinon, J., Egle, A. and Villunger, A. Apoptosis of leukocytes triggered by acute DNA damage promotes lymphoma formation. Genes Dev. 25 (2010) 1602–1607.

    Article  CAS  Google Scholar 

  107. Michalak, E.M., Vandenberg, C.J., Delbridge, A.R.D., Wu, L., Scott, C.L., Adams, J.M. and Strasser, A. Apoptosis-promoted tumorgenesis: γ-irradiation-induced thymic lymphpomagenesis requires Puma-driven leukocyte death. Genes Dev. 24 (2010) 1608–1613.

    PubMed  CAS  Article  Google Scholar 

  108. Qiu, W., Wang, X., Leibowitz, B., Yang, W., Zhang, L. and Yu, J. PUMAmediated apoptosis drives chemical hepatocarcinogenesis in mice. Hepatology 54 (2011) 1249–1258.

    PubMed  CAS  Article  Google Scholar 

  109. Llambi, F. and Green, D.R. Apoptosis and oncogenesis: give and take in the BLC-2 family. Curr. Opin. Genet. Dev. 21 (2011) 12–20.

    PubMed  CAS  Article  Google Scholar 

  110. Li, F., Huang, Q., Chen, J., Peng, Y., Roop, D., Bedford, J.S. and Li, C-Y. Apoptotic cells activate the “phoenix rising” pathway to promote wound healing and tissue regeneration. Sci. Signal. 3 (2010) 10.1126/scisignal.2000634.

  111. Baumgartner, F., Villunger, A. Apoptosis: a barrier against cancer no more? Hepatology 54 (2011) 1121–1124.

    PubMed  Article  Google Scholar 

  112. Labi, V. and Villunger, A. PUMA-mediated tumor suppression. Cell cycle 9 (2010) 4269–4275.

    PubMed  CAS  Article  Google Scholar 

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Correspondence to Zofia M. Kiliańska.

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Hikisz, P., Kiliańska, Z.M. Puma, a critical mediator of cell death — one decade on from its discovery. Cell Mol Biol Lett 17, 646–669 (2012). https://doi.org/10.2478/s11658-012-0032-5

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Key words

  • Apoptosis
  • BH3-only proteins
  • Carcinogenesis
  • Inhibitory members of the Bcl-2 family
  • Intrinsic apoptosis pathway
  • p53
  • Pro-apoptotic members of Bcl-2 family
  • PUMA
  • Post-translational regulation
  • Transcription factors