P53 upregulated modulator of apoptosis

Last updated
BBC3
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases BBC3 , JFY-1, JFY1, PUMA, BCL2 binding component 3
External IDs OMIM: 605854 MGI: 2181667 HomoloGene: 8679 GeneCards: BBC3
Orthologs
SpeciesHumanMouse
Entrez

27113

170770

Ensembl

ENSG00000105327

ENSMUSG00000002083

UniProt

Q96PG8
Q9BXH1

Q99ML1

RefSeq (mRNA)

NM_001127240
NM_001127241
NM_001127242
NM_014417

RefSeq (protein)
Location (UCSC) Chr 19: 47.22 – 47.23 Mb Chr 7: 16.04 – 16.05 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. [5] [6] In humans, the Bcl-2-binding component 3 protein is encoded by the BBC3 gene. [5] [6] 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. [7]

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. [5] 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. [8] The mitochondrial localization of PUMA is dictated by a hydrophobic domain on its C-terminal portion. [9] 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, [10] 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. [5]

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. [11] [12] Various studies have shown though, that PUMA does not rely on direct interaction with Bax/Bak to induce apoptosis. [13] [14]

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 [15] 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, [16] [17] proteasome inhibitors, [18] microtubule poisons, [19] and transcription inhibitors. [20] PUMA apoptosis may also be induced independently of p53 activation by other stimuli, such as oncogenic stress [21] [22] growth factor and/or cytokine withdrawal and kinase inhibition, [6] [23] [24] ER stress, altered redox status, [25] [26] ischemia, [11] [27] immune modulation, [28] [29] and infection. [7] [30]

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. [31] PUMA protein is degraded in a proteasome dependent manner and its degradation is regulated by phosphorylation at a conserved serine residue at position 10. [32]

Role in cancer

Several studies have shown that PUMA function is affected or absent in cancer cells. Additionally, many human tumors contain p53 mutations, [33] which results in no induction of PUMA, even after DNA damage induced through irradiation or chemotherapy drugs. [34] Other cancers, which exhibit overexpression of antiapoptotic Bcl-2 family proteins, counteract and overpower PUMA-induced apoptosis. [35] 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. [36] [37] [38] 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. [39] [40] [41] [42] [43] 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. [7]

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. [44]

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. [7]

Cancer treatments

Research has shown that increased PUMA expression with or without chemotherapy or irradiation is highly toxic to cancer cells, specifically lung, [45] head and neck, [46] esophagus, [47] melanoma, [48] malignant glioma, [49] gastric glands, [50] breast [51] and prostate. [52] In addition, studies have shown that PUMA adenovirus seems to induce apoptosis more so than p53 adenovirus. [45] [46] [47] This is beneficial in combating cancers that inhibit p53 activation and therefore indirectly decrease PUMA expression levels. [7]

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. [53]

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. [7] [35] [54]

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. [12] [55] 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. [7]

See also

Related Research Articles

<span class="mw-page-title-main">Apoptosis</span> Programmed cell death in multicellular organisms

Apoptosis is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, DNA fragmentation, and mRNA decay. The average adult human loses between 50 and 70 billion cells each day due to apoptosis. For an average human child between eight and fourteen years old, each day the approximate loss is 20 to 30 billion cells.

<span class="mw-page-title-main">Bcl-2</span> Protein found in humans

Bcl-2, encoded in humans by the BCL2 gene, is the founding member of the Bcl-2 family of regulator proteins that regulate cell death (apoptosis), by either inhibiting (anti-apoptotic) or inducing (pro-apoptotic) apoptosis. It was the first apoptosis regulator identified in any organism.

<span class="mw-page-title-main">Apoptosis regulator BAX</span> Mammalian protein found in Homo sapiens

Apoptosis regulator BAX, also known as bcl-2-like protein 4, is a protein that in humans is encoded by the BAX gene. BAX is a member of the Bcl-2 gene family. BCL2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein forms a heterodimer with BCL2, and functions as an apoptotic activator. This protein is reported to interact with, and increase the opening of, the mitochondrial voltage-dependent anion channel (VDAC), which leads to the loss in membrane potential and the release of cytochrome c. The expression of this gene is regulated by the tumor suppressor P53 and has been shown to be involved in P53-mediated apoptosis.

Adenovirus E1B protein usually refers to one of two proteins transcribed from the E1B gene of the adenovirus: a 55kDa protein and a 19kDa protein. These two proteins are needed to block apoptosis in adenovirus-infected cells. E1B proteins work to prevent apoptosis that is induced by the small adenovirus E1A protein, which stabilizes p53, a tumor suppressor.

<span class="mw-page-title-main">BH3 interacting-domain death agonist</span> Protein-coding gene in the species Homo sapiens

The BH3 interacting-domain death agonist, or BID, gene is a pro-apoptotic member of the Bcl-2 protein family. Bcl-2 family members share one or more of the four characteristic domains of homology entitled the Bcl-2 homology (BH) domains, and can form hetero- or homodimers. Bcl-2 proteins act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities.

<span class="mw-page-title-main">Phorbol-12-myristate-13-acetate-induced protein 1</span> Protein-coding gene in the species Homo sapiens

Phorbol-12-myristate-13-acetate-induced protein 1 is a protein that in humans is encoded by the PMAIP1 gene, and is also known as Noxa.

<span class="mw-page-title-main">Bcl-2 homologous antagonist killer</span> Protein-coding gene in the species Homo sapiens

Bcl-2 homologous antagonist/killer is a protein that in humans is encoded by the BAK1 gene on chromosome 6. The protein encoded by this gene belongs to the BCL2 protein family. BCL2 family members form oligomers or heterodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein localizes to mitochondria, and functions to induce apoptosis. It interacts with and accelerates the opening of the mitochondrial voltage-dependent anion channel, which leads to a loss in membrane potential and the release of cytochrome c. This protein also interacts with the tumor suppressor P53 after exposure to cell stress.

<span class="mw-page-title-main">Bcl-2-associated death promoter</span>

The BCL2 associated agonist of cell death (BAD) protein is a pro-apoptotic member of the Bcl-2 gene family which is involved in initiating apoptosis. BAD is a member of the BH3-only family, a subfamily of the Bcl-2 family. It does not contain a C-terminal transmembrane domain for outer mitochondrial membrane and nuclear envelope targeting, unlike most other members of the Bcl-2 family. After activation, it is able to form a heterodimer with anti-apoptotic proteins and prevent them from stopping apoptosis.

<span class="mw-page-title-main">Bcl-xL</span> Transmembrane molecule in the mitochondria

B-cell lymphoma-extra large (Bcl-xL), encoded by the BCL2-like 1 gene, is a transmembrane molecule in the mitochondria. It is a member of the Bcl-2 family of proteins, and acts as an anti-apoptotic protein by preventing the release of mitochondrial contents such as cytochrome c, which leads to caspase activation and ultimately, programmed cell death.

<span class="mw-page-title-main">Bcl-2-like protein 1</span> Protein-coding gene in the species Homo sapiens

Bcl-2-like protein 1 is a protein encoded in humans by the BCL2L1 gene. Through alternative splicing, the gene encodes both of the human proteins Bcl-xL and Bcl-xS.

<span class="mw-page-title-main">MCL1</span> Protein-coding gene in the species Homo sapiens

Induced myeloid leukemia cell differentiation protein Mcl-1 is a protein that in humans is encoded by the MCL1 gene.

<span class="mw-page-title-main">BNIP3</span> Protein-coding gene in the species Homo sapiens

BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 is a protein found in humans that is encoded by the BNIP3 gene.

<span class="mw-page-title-main">BCL2L11</span> Protein-coding gene in the species Homo sapiens

Bcl-2-like protein 11, commonly called BIM, is a protein that in humans is encoded by the BCL2L11 gene.

<span class="mw-page-title-main">Diablo homolog</span> Protein-coding gene in the species Homo sapiens

Diablo homolog (DIABLO) is a mitochondrial protein that in humans is encoded by the DIABLO gene on chromosome 12. DIABLO is also referred to as second mitochondria-derived activator of caspases or SMAC. This protein binds inhibitor of apoptosis proteins (IAPs), thus freeing caspases to activate apoptosis. Due to its proapoptotic function, SMAC is implicated in a broad spectrum of tumors, and small molecule SMAC mimetics have been developed to enhance current cancer treatments.

<span class="mw-page-title-main">Bcl-2-interacting killer</span> Protein-coding gene in the species Homo sapiens

Bcl-2-interacting killer is a protein that in humans is encoded by the BIK gene.

<span class="mw-page-title-main">BCL2L2</span> Protein-coding gene in the species Homo sapiens

Bcl-2-like protein 2 is a 193-amino acid protein that in humans is encoded by the BCL2L2 gene on chromosome 14. It was originally discovered by Leonie Gibson, Suzanne Cory and colleagues at the Walter and Eliza Hall Institute of Medical Research, who called it Bcl-w.

<span class="mw-page-title-main">HRK (gene)</span>

Activator of apoptosis harakiri is a protein that in humans is encoded by the HRK gene.

<span class="mw-page-title-main">BMF (gene)</span> Protein-coding gene in the species Homo sapiens

Bcl-2-modifying factor is a protein that in humans is encoded by the BMF gene.

<span class="mw-page-title-main">BOK (gene)</span> Protein-coding gene in the species Homo sapiens

Bok is a protein-coding gene of the Bcl-2 family that is found in many invertebrates and vertebrates. It induces apoptosis, a special type of cell death. Currently, the precise function of Bok in this process is unknown.

<span class="mw-page-title-main">Bcl-2 family</span>

The Bcl-2 family consists of a number of evolutionarily-conserved proteins that share Bcl-2 homology (BH) domains. The Bcl-2 family is most notable for their regulation of apoptosis, a form of programmed cell death, at the mitochondrion. The Bcl-2 family proteins consists of members that either promote or inhibit apoptosis, and control apoptosis by governing mitochondrial outer membrane permeabilization (MOMP), which is a key step in the intrinsic pathway of apoptosis. A total of 25 genes in the Bcl-2 family were identified by 2008.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000105327 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000002083 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 3 4 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.
  6. 1 2 3 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. Bibcode:2001PNAS...9811318H. doi: 10.1073/pnas.201208798 . PMC   58727 . PMID   11572983.
  7. 1 2 3 4 5 6 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.
  8. ↑ 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.
  9. ↑ 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. Bibcode:2003PNAS..100.1931Y. doi: 10.1073/pnas.2627984100 . PMC   149936 . PMID   12574499.
  10. ↑ Heckmeier PJ, Ruf J, Janković BG, Hamm P (7 March 2023). "MCL-1 promiscuity and the structural resilience of its binding partners". The Journal of Chemical Physics. 158 (9). arXiv: 2211.08934 . Bibcode:2023JChPh.158i5101H. doi: 10.1063/5.0137239 . PMID   36889945.
  11. 1 2 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.
  12. 1 2 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.
  13. ↑ 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. S2CID   1223271.
  14. ↑ 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. Bibcode:2007Sci...315..856W. doi:10.1126/science.1133289. PMID   17289999. S2CID   13300521.
  15. ↑ 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.
  16. ↑ 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. S2CID   11175215.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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. Bibcode:2002PNAS...9910855G. doi: 10.1073/pnas.132275599 . PMC   125062 . PMID   12145320.
  20. ↑ 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. S2CID   43760689.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ 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.
  25. ↑ 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.
  26. ↑ 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. S2CID   2997826.
  27. ↑ 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.
  28. ↑ 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. Bibcode:2006PNAS..10310979B. doi: 10.1073/pnas.0603625103 . PMC   1544160 . PMID   16832056.
  29. ↑ 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.
  30. ↑ 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.
  31. ↑ 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. S2CID   19355084.
  32. ↑ 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.
  33. ↑ 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. S2CID   205383514.
  34. ↑ 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.
  35. 1 2 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.
  36. ↑ 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.
  37. ↑ 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. S2CID   6313836.
  38. ↑ 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.
  39. ↑ 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.
  40. ↑ 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. Bibcode:2003Sci...302.1036V. doi:10.1126/science.1090072. PMID   14500851. S2CID   35505384.
  41. ↑ 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. Bibcode:2004PNAS..101.9333H. doi: 10.1073/pnas.0403286101 . PMC   438977 . PMID   15192153.
  42. ↑ 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.
  43. ↑ 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.
  44. ↑ 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.
  45. 1 2 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.
  46. 1 2 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.
  47. 1 2 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.
  48. ↑ 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.
  49. ↑ 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.
  50. ↑ 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. S2CID   22313616.
  51. ↑ 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. S2CID   25068339.
  52. ↑ 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.
  53. ↑ 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.
  54. ↑ 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.
  55. ↑ 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. S2CID   13472437.
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