P53 upregulated modulator of apoptosis

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The p53 upregulated modulator of apoptosis (PUMA) also known as Bcl-2-binding component 3 (BBC3), is a pro-apoptotic protein, member of the Bcl-2 protein family.[1][2] In humans, the Bcl-2-binding component 3 protein is encoded by the BBC3 gene.[1][2]

The expression of PUMA is regulated by the tumor suppressor p53. PUMA is involved in p53-dependent and -independent apoptosis induced by a variety of signals, and is regulated by transcription factors, not by post-translational modifications. After activation, PUMA interacts with antiapoptotic Bcl-2 family members, thus freeing Bax and/or Bak which are then able to signal apoptosis to the mitochondria. Following mitochondrial dysfunction, the caspase cascade is activated ultimately leading to cell death.[3]

## Contents

* 1 Structure
* 2 Mechanism of action
* 3 Regulation
* 3.1 Induction
* 3.2 Degradation
* 4 Role in cancer
* 5 Cancer therapeutics
* 5.1 Cancer treatments
* 5.2 Side-effect treatment
* 6 See also
* 7 References

## Structure

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The PUMA protein is part of the BH3-only subgroup of Bcl-2 family proteins. This group of proteins only share sequence similarity in the BH3 domain, which is required for interactions with Bcl-2-like proteins, such as Bcl-2 and Bcl-xL.[1] Structural analysis has shown that PUMA directly binds to antiapoptotic Bcl-2 family proteins via an amphiphatic α-helical structure which is formed by the BH3 domain.[4] The mitochondrial localization of PUMA is dictated by a hydrophobic domain on its C-terminal portion.[5] No posttranslational modification of PUMA has been discovered yet.[3]

## Mechanism of action

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Biochemical studies have shown that PUMA interacts with antiapoptotic Bcl-2 family members such as Bcl-xL, Bcl-2, Mcl-1, Bcl-w, and A1, inhibiting their interaction with the proapoptotic molecules, Bax and Bak. When the inhibition of these is lifted, they result in the translocation of Bax and activation of mitochondrial dysfunction resulting in release of mitochondrial apoptogenic proteins cytochrome c, SMAC, and apoptosis-inducing factor (AIF) leading to caspase activation and cell death.[1]

Because PUMA has high affinity for binding to Bcl-2 family members, another hypothesis is that PUMA directly activates Bax and/or Bak and through Bax multimerization triggers mitochondrial translocation and with it induces apoptosis.[6][7] Various studies have shown though, that PUMA does not rely on direct interaction with Bax/Bak to induce apoptosis.[8][9]

## Regulation

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### Induction

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The majority of PUMA induced apoptosis occurs through activation of the tumor suppressor protein p53. p53 is activated by survival signals such as glucose deprivation[10] and increases expression levels of PUMA. This increase in PUMA levels induces apoptosis through mitochondrial dysfunction. p53, and with it PUMA, is activated due to DNA damage caused by a variety of genotoxic agents. Other agents that induce p53 dependent apoptosis are neurotoxins,[11][12] proteasome inhibitors,[13] microtubule poisons,[14] and transcription inhibitors.[15] PUMA apoptosis may also be induced independently of p53 activation by other stimuli, such as oncogenic stress[16][17] growth factor and/or cytokine withdrawal and kinase inhibition,[2][18][19] ER stress, altered redox status,[20][21] ischemia,[6][22] immune modulation,[23][24] and infection.[3][25]

### Degradation

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PUMA levels are downregulated through the activation of caspase-3 and a protease inhibited by the serpase inhibitor N-tosyl-L-phenylalanine chloromethyl ketone, in response to signals such as the cytokine TGFβ, the death effector TRAIL or chemical drugs such as anisomycin.[26] PUMA protein is degraded in a proteasome dependent manner and its degradation is regulated by phosphorylation at a conserved serine residue at position 10.[27]

## Role in cancer

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Several studies have shown that PUMA function is affected or absent in cancer cells. Additionally, many human tumors contain p53 mutations,[28] which results in no induction of PUMA, even after DNA damage induced through irradiation or chemotherapy drugs.[29] Other cancers, which exhibit overexpression of antiapoptotic Bcl-2 family proteins, counteract and overpower PUMA-induced apoptosis.[30] Even though PUMA function is compromised in most cancer cells, it does not appear that genetic inactivation of PUMA is a direct target of cancer.[31][32][33] Many cancers do exhibit p53 gene mutations, making gene therapies that target this gene [clarification needed] impossible, but an alternate pathway may be to focus on therapeutic to target PUMA and induce apoptosis in cancer cells. Animal studies have shown that PUMA does play a role in tumor suppression, but lack of PUMA activity alone does not translate to spontaneous formation of malignancies.[34][35][36][37][38] Inhibiting PUMA induced apoptosis may be an interesting target for reducing the side effects of cancer treatments, such as chemotherapy, which induce apoptosis in rapidly dividing healthy cells in addition to rapidly dividing cancer cells.[3]

PUMA can also function as an indicator of p53 mutations. Many cancers exhibit mutations in the p53 gene, but this mutation can only be detected through extensive DNA sequencing. Studies have shown that cells with p53 mutations have significantly lower levels of PUMA, making it a good candidate for a protein marker of p53 mutations, providing a simpler method for testing for p53 mutations.[39]

## Cancer therapeutics

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Therapeutic agents targeting PUMA for cancer patients are emerging. PUMA inducers target cancer or tumor cells, while PUMA inhibitors can be targeted to normal, healthy cells to help alleviate the undesired side effects of chemo and radiation therapy.[3]

### Cancer treatments

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Research has shown that increased PUMA expression with or without chemotherapy or irradiation is highly toxic to cancer cells, specifically lung,[40] head and neck,[41] esophagus,[42] melanoma,[43] malignant glioma,[44] gastric glands,[45] breast[46] and prostate.[47] In addition, studies have shown that PUMA adenovirus seems to induce apoptosis more so than p53 adenovirus.[40][41][42] This is beneficial in combating cancers that inhibit p53 activation and therefore indirectly decrease PUMA expression levels.[3]

Resveratrol, a plant-derived stilbenoid, is currently under investigation as a cancer treatment. Resveratrol acts to inhibit and decrease expression of antiapoptotic Bcl-2 family members while also increasing p53 expression. The combination of these two mechanisms leads to apoptosis via activation of PUMA, Noxa and other proapoptotic proteins, resulting in mitochondrial dysfunction.[48]

Other approaches focus on inhibiting antiapoptotic Bcl-2 family members just as PUMA does, allowing cells to undergo apoptosis in response to cancerous activity. Preclinical studies involving these inhibitors, also described as BH3 mimetics, have produced promising results.[3][30][49]

### Side-effect treatment

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Irradiation therapy is dose-limited by undesired side effects in healthy tissue. PUMA has been shown to be active in inducing apoptosis in hematopoietic and intestinal tissue following γ-irradiation.[7][50] Since inhibition of PUMA does not directly cause spontaneous malignancies, therapeutics to inhibit PUMA function in healthy tissue could lessen or eliminate the side effects of traditional cancer therapies.[3]

## See also

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* Apoptosis
* Apoptosome
* Bcl-2
* Bcl-2-associated X protein (BAX)
* BH3 interacting domain death agonist (BID)
* Caspases
* Cytochrome c
* Noxa
* Mitochondrion

## References

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1. ↑ 1.0 1.1 1.2 1.3 Nakano K, Vousden KH (March 2001). "PUMA, a novel proapoptotic gene, is induced by p53". Mol. Cell. 7 (3): 683–94. doi:10.1016/S1097-2765(01)00214-3. PMID 11463392.
2. ↑ 2.0 2.1 2.2 Han J, Flemington C, Houghton AB, Gu Z, Zambetti GP, Lutz RJ, Zhu L, Chittenden T (September 2001). "Expression of bbc3, a pro-apoptotic BH3-only gene, is regulated by diverse cell death and survival signals". Proc. Natl. Acad. Sci. U.S.A. 98 (20): 11318–23. doi:10.1073/pnas.201208798. PMC 58727. PMID 11572983.
3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 Yu J, Zhang L (December 2008). "PUMA, a potent killer with or without p53". Oncogene. 27 Suppl 1: S71–83. doi:10.1038/onc.2009.45. PMC 2860432. PMID 19641508.
4. ↑ Day CL, Smits C, Fan FC, Lee EF, Fairlie WD, Hinds MG (July 2008). "Structure of the BH3 domains from the p53-inducible BH3-only proteins Noxa and Puma in complex with Mcl-1". J. Mol. Biol. 380 (5): 958–71. doi:10.1016/j.jmb.2008.05.071. PMID 18589438.
5. ↑ Yu J, Wang Z, Kinzler KW, Vogelstein B, Zhang L (February 2003). "PUMA mediates the apoptotic response to p53 in colorectal cancer cells". Proc. Natl. Acad. Sci. U.S.A. 100 (4): 1931–6. doi:10.1073/pnas.2627984100. PMC 149936. PMID 12574499.
6. ↑ 6.0 6.1 Wu B, Qiu W, Wang P, Yu H, Cheng T, Zambetti GP, Zhang L, Yu J (May 2007). "p53 independent induction of PUMA mediates intestinal apoptosis in response to ischaemia-reperfusion". Gut. 56 (5): 645–54. doi:10.1136/gut.2006.101683. PMC 1942137. PMID 17127703.
7. ↑ 7.0 7.1 Qiu W, Carson-Walter EB, Liu H, Epperly M, Greenberger JS, Zambetti GP, Zhang L, Yu J (June 2008). "PUMA regulates intestinal progenitor cell radiosensitivity and gastrointestinal syndrome". Cell Stem Cell. 2 (6): 576–83. doi:10.1016/j.stem.2008.03.009. PMC 2892934. PMID 18522850.
8. ↑ Yee KS, Vousden KH (January 2008). "Contribution of membrane localization to the apoptotic activity of PUMA". Apoptosis. 13 (1): 87–95. doi:10.1007/s10495-007-0140-2. PMID 17968660.
9. ↑ Willis SN, Fletcher JI, Kaufmann T, van Delft MF, Chen L, Czabotar PE, Ierino H, Lee EF, Fairlie WD, Bouillet P, Strasser A, Kluck RM, Adams JM, Huang DC (February 2007). "Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak". Science. 315 (5813): 856–9. doi:10.1126/science.1133289. PMID 17289999.
10. ↑ Zhao Y, Coloff JL, Ferguson EC, Jacobs SR, Cui K, Rathmell JC (December 2008). "Glucose metabolism attenuates p53 and Puma-dependent cell death upon growth factor deprivation". J. Biol. Chem. 283 (52): 36344–53. doi:10.1074/jbc.M803580200. PMC 2606014. PMID 18990690.
11. ↑ Gomez-Lazaro M, Galindo MF, Fernandez-Gomez FJ, Prehn JH, Jordán J (November 2005). "Activation of p53 and the pro-apoptotic p53 target gene PUMA during depolarization-induced apoptosis of chromaffin cells". Exp. Neurol. 196 (1): 96–103. doi:10.1016/j.expneurol.2005.07.011. PMID 16112113.
12. ↑ Wong HK, Fricker M, Wyttenbach A, Villunger A, Michalak EM, Strasser A, Tolkovsky AM (October 2005). "Mutually exclusive subsets of BH3-only proteins are activated by the p53 and c-Jun N-terminal kinase/c-Jun signaling pathways during cortical neuron apoptosis induced by arsenite". Mol. Cell. Biol. 25 (19): 8732–47. doi:10.1128/MCB.25.19.8732-8747.2005. PMC 1265744. PMID 16166651.
13. ↑ Yu J, Wang P, Ming L, Wood MA, Zhang L (June 2007). "SMAC/Diablo mediates the proapoptotic function of PUMA by regulating PUMA-induced mitochondrial events". Oncogene. 26 (29): 4189–98. doi:10.1038/sj.onc.1210196. PMID 17237824.
14. ↑ Giannakakou P, Nakano M, Nicolaou KC, O'Brate A, Yu J, Blagosklonny MV, Greber UF, Fojo T (August 2002). "Enhanced microtubule-dependent trafficking and p53 nuclear accumulation by suppression of microtubule dynamics". Proc. Natl. Acad. Sci. U.S.A. 99 (16): 10855–60. doi:10.1073/pnas.132275599. PMC 125062. PMID 12145320.
15. ↑ Kalousek I, Brodska B, Otevrelova P, Röselova P (August 2007). "Actinomycin D upregulates proapoptotic protein Puma and downregulates Bcl-2 mRNA in normal peripheral blood lymphocytes". Anticancer Drugs. 18 (7): 763–72. doi:10.1097/CAD.0b013e3280adc905. PMID 17581298.
16. ↑ Fernandez PC, Frank SR, Wang L, Schroeder M, Liu S, Greene J, Cocito A, Amati B (May 2003). "Genomic targets of the human c-Myc protein". Genes Dev. 17 (9): 1115–29. doi:10.1101/gad.1067003. PMC 196049. PMID 12695333.
17. ↑ Maclean KH, Keller UB, Rodriguez-Galindo C, Nilsson JA, Cleveland JL (October 2003). "c-Myc augments gamma irradiation-induced apoptosis by suppressing Bcl-XL". Mol. Cell. Biol. 23 (20): 7256–70. doi:10.1128/mcb.23.20.7256-7270.2003. PMC 230315. PMID 14517295.
18. ↑ You H, Pellegrini M, Tsuchihara K, Yamamoto K, Hacker G, Erlacher M, Villunger A, Mak TW (July 2006). "FOXO3a-dependent regulation of Puma in response to cytokine/growth factor withdrawal". J. Exp. Med. 203 (7): 1657–63. doi:10.1084/jem.20060353. PMC 2118330. PMID 16801400.
19. ↑ Ming L, Sakaida T, Yue W, Jha A, Zhang L, Yu J (October 2008). "Sp1 and p73 activate PUMA following serum starvation". Carcinogenesis. 29 (10): 1878–84. doi:10.1093/carcin/bgn150. PMC 2722853. PMID 18579560.
20. ↑ Reimertz C, Kögel D, Rami A, Chittenden T, Prehn JH (August 2003). "Gene expression during ER stress-induced apoptosis in neurons: induction of the BH3-only protein Bbc3/PUMA and activation of the mitochondrial apoptosis pathway". J. Cell Biol. 162 (4): 587–97. doi:10.1083/jcb.200305149. PMC 2173793. PMID 12913114.
21. ↑ Ward MW, Kögel D, Prehn JH (August 2004). "Neuronal apoptosis: BH3-only proteins the real killers?". J. Bioenerg. Biomembr. 36 (4): 295–8. doi:10.1023/B:JOBB.0000041756.23918.11. PMID 15377860.
22. ↑ Webster KA (July 2006). "Puma joins the battery of BH3-only proteins that promote death and infarction during myocardial ischemia". Am. J. Physiol. Heart Circ. Physiol. 291 (1): H20–2. doi:10.1152/ajpheart.00111.2006. PMID 16772523.
23. ↑ Bauer A, Villunger A, Labi V, Fischer SF, Strasser A, Wagner H, Schmid RM, Häcker G (July 2006). "The NF-kappaB regulator Bcl-3 and the BH3-only proteins Bim and Puma control the death of activated T cells". Proc. Natl. Acad. Sci. U.S.A. 103 (29): 10979–84. doi:10.1073/pnas.0603625103. PMC 1544160. PMID 16832056.
24. ↑ Fischer SF, Vier J, Kirschnek S, Klos A, Hess S, Ying S, Häcker G (October 2004). "Chlamydia inhibit host cell apoptosis by degradation of proapoptotic BH3-only proteins". J. Exp. Med. 200 (7): 905–16. doi:10.1084/jem.20040402. PMC 2213288. PMID 15452181.
25. ↑ Castedo M, Perfettini JL, Piacentini M, Kroemer G (June 2005). "p53-A pro-apoptotic signal transducer involved in AIDS". Biochem. Biophys. Res. Commun. 331 (3): 701–6. doi:10.1016/j.bbrc.2005.03.188. PMID 15865925.
26. ↑ Hadji A, Clybouw C, Auffredou MT, Alexia C, Poalas K, Burlion A, Feraud O, Leca G, Vazquez A (December 2010). "Caspase-3 triggers a TPCK-sensitive protease pathway leading to degradation of the BH3-only protein puma". Apoptosis. 15 (12): 1529–39. doi:10.1007/s10495-010-0528-2. PMID 20640889.
27. ↑ Fricker M, O'Prey J, Tolkovsky AM, Ryan KM (July 2010). "Phosphorylation of Puma modulates its apoptotic function by regulating protein stability". Cell Death & Disease. 1 (e59): e59. doi:10.1038/cddis.2010.38. PMC 3032554. PMID 21364664.
28. ↑ Vogelstein B, Kinzler KW (August 2004). "Cancer genes and the pathways they control". Nat. Med. 10 (8): 789–99. doi:10.1038/nm1087. PMID 15286780.
29. ↑ Yu J, Zhang L (June 2005). "The transcriptional targets of p53 in apoptosis control". Biochem. Biophys. Res. Commun. 331 (3): 851–8. doi:10.1016/j.bbrc.2005.03.189. PMID 15865941.
30. ↑ 30.0 30.1 Adams JM, Cory S (February 2007). "The Bcl-2 apoptotic switch in cancer development and therapy". Oncogene. 26 (9): 1324–37. doi:10.1038/sj.onc.1210220. PMC 2930981. PMID 17322918.
31. ↑ Hoque MO, Begum S, Sommer M, Lee T, Trink B, Ratovitski E, Sidransky D (September 2003). "PUMA in head and neck cancer". Cancer Lett. 199 (1): 75–81. doi:10.1016/S0304-3835(03)00344-6. PMID 12963126.
32. ↑ Kim MR, Jeong EG, Chae B, Lee JW, Soung YH, Nam SW, Lee JY, Yoo NJ, Lee SH (October 2007). "Pro-apoptotic PUMA and anti-apoptotic phospho-BAD are highly expressed in colorectal carcinomas". Dig. Dis. Sci. 52 (10): 2751–6. doi:10.1007/s10620-007-9799-z. PMID 17393317.
33. ↑ Yoo NJ, Lee JW, Jeong EG, Lee SH (March 2007). "Immunohistochemical analysis of pro-apoptotic PUMA protein and mutational analysis of PUMA gene in gastric carcinomas". Dig Liver Dis. 39 (3): 222–7. doi:10.1016/j.dld.2006.11.006. PMID 17267315.
34. ↑ Jeffers JR, Parganas E, Lee Y, Yang C, Wang J, Brennan J, MacLean KH, Han J, Chittenden T, Ihle JN, McKinnon PJ, Cleveland JL, Zambetti GP (October 2003). "Puma is an essential mediator of p53-dependent and -independent apoptotic pathways". Cancer Cell. 4 (4): 321–8. doi:10.1016/S1535-6108(03)00244-7. PMID 14585359.
35. ↑ Villunger A, Michalak EM, Coultas L, Müllauer F, Böck G, Ausserlechner MJ, Adams JM, Strasser A (November 2003). "p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa". Science. 302 (5647): 1036–8. doi:10.1126/science.1090072. PMID 14500851.
36. ↑ Hemann MT, Zilfou JT, Zhao Z, Burgess DJ, Hannon GJ, Lowe SW (June 2004). "Suppression of tumorigenesis by the p53 target PUMA". Proc. Natl. Acad. Sci. U.S.A. 101 (25): 9333–8. doi:10.1073/pnas.0403286101. PMC 438977. PMID 15192153.
37. ↑ Erlacher M, Labi V, Manzl C, Böck G, Tzankov A, Häcker G, Michalak E, Strasser A, Villunger A (December 2006). "Puma cooperates with Bim, the rate-limiting BH3-only protein in cell death during lymphocyte development, in apoptosis induction". J. Exp. Med. 203 (13): 2939–51. doi:10.1084/jem.20061552. PMC 2118188. PMID 17178918.
38. ↑ Nelson DA, Tan TT, Rabson AB, Anderson D, Degenhardt K, White E (September 2004). "Hypoxia and defective apoptosis drive genomic instability and tumorigenesis". Genes Dev. 18 (17): 2095–107. doi:10.1101/gad.1204904. PMC 515288. PMID 15314031.
39. ↑ Hollstein M, Hupp T (May 2011). "Chek2ing out the p53 pathway: Can puma lead the way?". Cell Cycle. 10 (10): 1524. doi:10.4161/cc.10.10.15514. PMID 21478674.
40. ↑ 40.0 40.1 Yu J, Yue W, Wu B, Zhang L (May 2006). "PUMA sensitizes lung cancer cells to chemotherapeutic agents and irradiation". Clin. Cancer Res. 12 (9): 2928–36. doi:10.1158/1078-0432.CCR-05-2429. PMID 16675590.
41. ↑ 41.0 41.1 Sun Q, Sakaida T, Yue W, Gollin SM, Yu J (December 2007). "Chemosensitization of head and neck cancer cells by PUMA". Mol. Cancer Ther. 6 (12 Pt 1): 3180–8. doi:10.1158/1535-7163.MCT-07-0265. PMID 18089712.
42. ↑ 42.0 42.1 Wang H, Qian H, Yu J, Zhang X, Zhang L, Fu M, Liang X, Zhan Q, Lin C (April 2006). "Administration of PUMA adenovirus increases the sensitivity of esophageal cancer cells to anticancer drugs". Cancer Biol. Ther. 5 (4): 380–5. doi:10.4161/cbt.5.4.2477. PMID 16481741.
43. ↑ Karst AM, Dai DL, Cheng JQ, Li G (September 2006). "Role of p53 up-regulated modulator of apoptosis and phosphorylated Akt in melanoma cell growth, apoptosis, and patient survival". Cancer Res. 66 (18): 9221–6. doi:10.1158/0008-5472.CAN-05-3633. PMID 16982766.
44. ↑ Ito H, Kanzawa T, Miyoshi T, Hirohata S, Kyo S, Iwamaru A, Aoki H, Kondo Y, Kondo S (June 2005). "Therapeutic efficacy of PUMA for malignant glioma cells regardless of p53 status". Hum. Gene Ther. 16 (6): 685–98. doi:10.1089/hum.2005.16.685. PMC 1387050. PMID 15960600.
45. ↑ Dvory-Sobol H, Sagiv E, Liberman E, Kazanov D, Arber N (January 2007). "Suppression of gastric cancer cell growth by targeting the beta-catenin/T-cell factor pathway". Cancer. 109 (2): 188–97. doi:10.1002/cncr.22416. PMID 17149756.
46. ↑ Wang R, Wang X, Li B, Lin F, Dong K, Gao P, Zhang HZ (September 2009). "Tumor-specific adenovirus-mediated PUMA gene transfer using the survivin promoter enhances radiosensitivity of breast cancer cells in vitro and in vivo". Breast Cancer Res. Treat. 117 (1): 45–54. doi:10.1007/s10549-008-0163-6. PMID 18791823.
47. ↑ Giladi N, Dvory-Sobol H, Sagiv E, Kazanov D, Liberman E, Arber N (October 2007). "Gene therapy approach in prostate cancer cells using an active Wnt signal". Biomed. Pharmacother. 61 (9): 527–30. doi:10.1016/j.biopha.2007.08.010. PMID 17904788.
48. ↑ Athar M, Back JH, Kopelovich L, Bickers DR, Kim AL (June 2009). "Multiple molecular targets of resveratrol: Anti-carcinogenic mechanisms". Arch. Biochem. Biophys. 486 (2): 95–102. doi:10.1016/j.abb.2009.01.018. PMC 2749321. PMID 19514131.
49. ↑ Zhang L, Ming L, Yu J (December 2007). "BH3 mimetics to improve cancer therapy; mechanisms and examples". Drug Resist. Updat. 10 (6): 207–17. doi:10.1016/j.drup.2007.08.002. PMC 2265791. PMID 17921043.
50. ↑ Wu WS, Heinrichs S, Xu D, Garrison SP, Zambetti GP, Adams JM, Look AT (November 2005). "Slug antagonizes p53-mediated apoptosis of hematopoietic progenitors by repressing puma". Cell. 123 (4): 641–53. doi:10.1016/j.cell.2005.09.029. PMID 16286009.