Biology:p53 upregulated modulator of apoptosis

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Short description: Protein-coding gene in the species Homo sapiens

A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


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]

Structure

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] PUMA protein degradation is regulated by phosphorylation at a conserved serine residue at position 10.[31]

Mechanism of action

Biochemical studies have shown that PUMA interacts with antiapoptotic Bcl-2 family members such as Bcl-xL, Bcl-2, Mcl-1,[6] 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.[7][8] Various studies have shown though, that PUMA does not rely on direct interaction with Bax/Bak to induce apoptosis.[9][10]

Regulation

Induction

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[11] 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,[12][13] proteasome inhibitors,[14] microtubule poisons,[15] and transcription inhibitors.[16] PUMA apoptosis may also be induced independently of p53 activation by other stimuli, such as oncogenic stress[17][18] growth factor and/or cytokine withdrawal and kinase inhibition,[2][19][20] ER stress, altered redox status,[21][22] ischemia,[7][23] immune modulation,[24][25] and infection.[3][26]

Degradation

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.[27] PUMA protein is degraded in a proteasome dependent manner and its degradation is regulated by phosphorylation at a conserved serine residue at position 10.[28]

Role in cancer

Several studies have shown that PUMA function is affected or absent in cancer cells. Additionally, many human tumors contain p53 mutations,[29] which results in no induction of PUMA, even after DNA damage induced through irradiation or chemotherapy drugs.[30] Other cancers, which exhibit overexpression of antiapoptotic Bcl-2 family proteins, counteract and overpower PUMA-induced apoptosis.[31] 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.[32][33][34] 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.[35][36][37][38][39] 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.[40]

Cancer therapeutics

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

Research has shown that increased PUMA expression with or without chemotherapy or irradiation is highly toxic to cancer cells, specifically lung,[41] head and neck,[42] esophagus,[43] melanoma,[44] malignant glioma,[45] gastric glands,[46] breast[47] and prostate.[48] In addition, studies have shown that PUMA adenovirus seems to induce apoptosis more so than p53 adenovirus.[41][42][43] 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.[49]

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][31][50]

Side-effect treatment

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.[8][51] 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

References

  1. ↑ 1.0 1.1 1.2 1.3 "PUMA, a novel proapoptotic gene, is induced by p53". Mol. Cell 7 (3): 683–94. March 2001. doi:10.1016/S1097-2765(01)00214-3. PMID 11463392. 
  2. ↑ 2.0 2.1 2.2 "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. September 2001. doi:10.1073/pnas.201208798. PMID 11572983. Bibcode: 2001PNAS...9811318H. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 "PUMA, a potent killer with or without p53". Oncogene 27 (Suppl 1): S71–83. December 2008. doi:10.1038/onc.2009.45. PMID 19641508. 
  4. ↑ "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. July 2008. doi:10.1016/j.jmb.2008.05.071. PMID 18589438. 
  5. ↑ "PUMA mediates the apoptotic response to p53 in colorectal cancer cells". Proc. Natl. Acad. Sci. U.S.A. 100 (4): 1931–6. February 2003. doi:10.1073/pnas.2627984100. PMID 12574499. Bibcode: 2003PNAS..100.1931Y. 
  6. ↑ Heckmeier, Philipp J.; Ruf, Jeannette; Janković, Brankica G.; Hamm, Peter (7 March 2023). "MCL-1 promiscuity and the structural resilience of its binding partners". The Journal of Chemical Physics 158 (9). doi:10.1063/5.0137239. PMID 36889945. Bibcode: 2023JChPh.158i5101H. 
  7. ↑ 7.0 7.1 "p53 independent induction of PUMA mediates intestinal apoptosis in response to ischaemia-reperfusion". Gut 56 (5): 645–54. May 2007. doi:10.1136/gut.2006.101683. PMID 17127703. 
  8. ↑ 8.0 8.1 "PUMA regulates intestinal progenitor cell radiosensitivity and gastrointestinal syndrome". Cell Stem Cell 2 (6): 576–83. June 2008. doi:10.1016/j.stem.2008.03.009. PMID 18522850. 
  9. ↑ "Contribution of membrane localization to the apoptotic activity of PUMA". Apoptosis 13 (1): 87–95. January 2008. doi:10.1007/s10495-007-0140-2. PMID 17968660. 
  10. ↑ "Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak". Science 315 (5813): 856–9. February 2007. doi:10.1126/science.1133289. PMID 17289999. Bibcode: 2007Sci...315..856W. 
  11. ↑ "Glucose metabolism attenuates p53 and Puma-dependent cell death upon growth factor deprivation". J. Biol. Chem. 283 (52): 36344–53. December 2008. doi:10.1074/jbc.M803580200. PMID 18990690. 
  12. ↑ "Activation of p53 and the pro-apoptotic p53 target gene PUMA during depolarization-induced apoptosis of chromaffin cells". Exp. Neurol. 196 (1): 96–103. November 2005. doi:10.1016/j.expneurol.2005.07.011. PMID 16112113. 
  13. ↑ "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. October 2005. doi:10.1128/MCB.25.19.8732-8747.2005. PMID 16166651. 
  14. ↑ "SMAC/Diablo mediates the proapoptotic function of PUMA by regulating PUMA-induced mitochondrial events". Oncogene 26 (29): 4189–98. June 2007. doi:10.1038/sj.onc.1210196. PMID 17237824. 
  15. ↑ "Enhanced microtubule-dependent trafficking and p53 nuclear accumulation by suppression of microtubule dynamics". Proc. Natl. Acad. Sci. U.S.A. 99 (16): 10855–60. August 2002. doi:10.1073/pnas.132275599. PMID 12145320. Bibcode: 2002PNAS...9910855G. 
  16. ↑ "Actinomycin D upregulates proapoptotic protein Puma and downregulates Bcl-2 mRNA in normal peripheral blood lymphocytes". Anticancer Drugs 18 (7): 763–72. August 2007. doi:10.1097/CAD.0b013e3280adc905. PMID 17581298. 
  17. ↑ "Genomic targets of the human c-Myc protein". Genes Dev. 17 (9): 1115–29. May 2003. doi:10.1101/gad.1067003. PMID 12695333. 
  18. ↑ "c-Myc augments gamma irradiation-induced apoptosis by suppressing Bcl-XL". Mol. Cell. Biol. 23 (20): 7256–70. October 2003. doi:10.1128/mcb.23.20.7256-7270.2003. PMID 14517295. 
  19. ↑ "FOXO3a-dependent regulation of Puma in response to cytokine/growth factor withdrawal". J. Exp. Med. 203 (7): 1657–63. July 2006. doi:10.1084/jem.20060353. PMID 16801400. 
  20. ↑ "Sp1 and p73 activate PUMA following serum starvation". Carcinogenesis 29 (10): 1878–84. October 2008. doi:10.1093/carcin/bgn150. PMID 18579560. 
  21. ↑ "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. August 2003. doi:10.1083/jcb.200305149. PMID 12913114. 
  22. ↑ "Neuronal apoptosis: BH3-only proteins the real killers?". J. Bioenerg. Biomembr. 36 (4): 295–8. August 2004. doi:10.1023/B:JOBB.0000041756.23918.11. PMID 15377860. 
  23. ↑ 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. 
  24. ↑ "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. July 2006. doi:10.1073/pnas.0603625103. PMID 16832056. Bibcode: 2006PNAS..10310979B. 
  25. ↑ "Chlamydia inhibit host cell apoptosis by degradation of proapoptotic BH3-only proteins". J. Exp. Med. 200 (7): 905–16. October 2004. doi:10.1084/jem.20040402. PMID 15452181. 
  26. ↑ "p53-A pro-apoptotic signal transducer involved in AIDS". Biochem. Biophys. Res. Commun. 331 (3): 701–6. June 2005. doi:10.1016/j.bbrc.2005.03.188. PMID 15865925. 
  27. ↑ "Caspase-3 triggers a TPCK-sensitive protease pathway leading to degradation of the BH3-only protein puma". Apoptosis 15 (12): 1529–39. December 2010. doi:10.1007/s10495-010-0528-2. PMID 20640889. 
  28. ↑ "Phosphorylation of Puma modulates its apoptotic function by regulating protein stability.". Cell Death & Disease 1 (e59): e59. July 2010. doi:10.1038/cddis.2010.38. PMID 21364664. 
  29. ↑ "Cancer genes and the pathways they control". Nat. Med. 10 (8): 789–99. August 2004. doi:10.1038/nm1087. PMID 15286780. 
  30. ↑ "The transcriptional targets of p53 in apoptosis control". Biochem. Biophys. Res. Commun. 331 (3): 851–8. June 2005. doi:10.1016/j.bbrc.2005.03.189. PMID 15865941. 
  31. ↑ 31.0 31.1 "The Bcl-2 apoptotic switch in cancer development and therapy". Oncogene 26 (9): 1324–37. February 2007. doi:10.1038/sj.onc.1210220. PMID 17322918. 
  32. ↑ "PUMA in head and neck cancer". Cancer Lett. 199 (1): 75–81. September 2003. doi:10.1016/S0304-3835(03)00344-6. PMID 12963126. 
  33. ↑ "Pro-apoptotic PUMA and anti-apoptotic phospho-BAD are highly expressed in colorectal carcinomas". Dig. Dis. Sci. 52 (10): 2751–6. October 2007. doi:10.1007/s10620-007-9799-z. PMID 17393317. 
  34. ↑ "Immunohistochemical analysis of pro-apoptotic PUMA protein and mutational analysis of PUMA gene in gastric carcinomas". Dig Liver Dis 39 (3): 222–7. March 2007. doi:10.1016/j.dld.2006.11.006. PMID 17267315. 
  35. ↑ "Puma is an essential mediator of p53-dependent and -independent apoptotic pathways". Cancer Cell 4 (4): 321–8. October 2003. doi:10.1016/S1535-6108(03)00244-7. PMID 14585359. 
  36. ↑ "p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa". Science 302 (5647): 1036–8. November 2003. doi:10.1126/science.1090072. PMID 14500851. Bibcode: 2003Sci...302.1036V. 
  37. ↑ "Suppression of tumorigenesis by the p53 target PUMA". Proc. Natl. Acad. Sci. U.S.A. 101 (25): 9333–8. June 2004. doi:10.1073/pnas.0403286101. PMID 15192153. Bibcode: 2004PNAS..101.9333H. 
  38. ↑ "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. December 2006. doi:10.1084/jem.20061552. PMID 17178918. 
  39. ↑ "Hypoxia and defective apoptosis drive genomic instability and tumorigenesis". Genes Dev. 18 (17): 2095–107. September 2004. doi:10.1101/gad.1204904. PMID 15314031. 
  40. ↑ "Chek2ing out the p53 pathway: Can puma lead the way?". Cell Cycle 10 (10): 1524. May 2011. doi:10.4161/cc.10.10.15514. PMID 21478674. 
  41. ↑ 41.0 41.1 "PUMA sensitizes lung cancer cells to chemotherapeutic agents and irradiation". Clin. Cancer Res. 12 (9): 2928–36. May 2006. doi:10.1158/1078-0432.CCR-05-2429. PMID 16675590. 
  42. ↑ 42.0 42.1 "Chemosensitization of head and neck cancer cells by PUMA". Mol. Cancer Ther. 6 (12 Pt 1): 3180–8. December 2007. doi:10.1158/1535-7163.MCT-07-0265. PMID 18089712. 
  43. ↑ 43.0 43.1 "Administration of PUMA adenovirus increases the sensitivity of esophageal cancer cells to anticancer drugs". Cancer Biol. Ther. 5 (4): 380–5. April 2006. doi:10.4161/cbt.5.4.2477. PMID 16481741. 
  44. ↑ "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. September 2006. doi:10.1158/0008-5472.CAN-05-3633. PMID 16982766. 
  45. ↑ "Therapeutic efficacy of PUMA for malignant glioma cells regardless of p53 status". Hum. Gene Ther. 16 (6): 685–98. June 2005. doi:10.1089/hum.2005.16.685. PMID 15960600. 
  46. ↑ "Suppression of gastric cancer cell growth by targeting the beta-catenin/T-cell factor pathway". Cancer 109 (2): 188–97. January 2007. doi:10.1002/cncr.22416. PMID 17149756. 
  47. ↑ "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. September 2009. doi:10.1007/s10549-008-0163-6. PMID 18791823. 
  48. ↑ "Gene therapy approach in prostate cancer cells using an active Wnt signal". Biomed. Pharmacother. 61 (9): 527–30. October 2007. doi:10.1016/j.biopha.2007.08.010. PMID 17904788. 
  49. ↑ "Multiple molecular targets of resveratrol: Anti-carcinogenic mechanisms". Arch. Biochem. Biophys. 486 (2): 95–102. June 2009. doi:10.1016/j.abb.2009.01.018. PMID 19514131. 
  50. ↑ "BH3 mimetics to improve cancer therapy; mechanisms and examples". Drug Resist. Updat. 10 (6): 207–17. December 2007. doi:10.1016/j.drup.2007.08.002. PMID 17921043. 
  51. ↑ "Slug antagonizes p53-mediated apoptosis of hematopoietic progenitors by repressing puma". Cell 123 (4): 641–53. November 2005. doi:10.1016/j.cell.2005.09.029. PMID 16286009. 

External links

  • Overview of all the structural information available in the PDB for UniProt: Q9BXH1 (Human Bcl-2-binding component 3, isoforms 1/2) at the PDBe-KB.
  • Overview of all the structural information available in the PDB for UniProt: Q99ML1 (Mouse Bcl-2-binding component 3) at the PDBe-KB.



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