Promyelocytic leukemia protein

PML
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1BOR, 2MVW, 2MWX, 4WJN, 4WJO
Identifiers
Aliases	PML, MYL, PP8675, RNF71, TRIM19, Promyelocytic leukemia protein, promyelocytic leukemia, Probable transcription factor PML
External IDs	MGI: 104662 HomoloGene: 13245 GeneCards: PML
Genetically Related Diseases
myopia, mammary Paget's disease[1]
Gene ontology Molecular function • SUMO binding • cobalt ion binding • metal ion binding • protein homodimerization activity • zinc ion binding • protein binding • SMAD binding • DNA binding • transcription coactivator activity • protein heterodimerization activity • ubiquitin protein ligase binding Cellular component • cytoplasm • cytosol • endosome • nuclear membrane • membrane • nuclear chromosome, telomeric region • nucleus • nuclear matrix • nucleolus • endoplasmic reticulum • early endosome membrane • intracellular • nucleoplasm • PML body • endoplasmic reticulum membrane • extrinsic component of endoplasmic reticulum membrane Biological process • regulation of protein phosphorylation • positive regulation of histone deacetylation • intrinsic apoptotic signaling pathway in response to oxidative stress • myeloid cell differentiation • DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest • negative regulation of telomere maintenance via telomerase • rhythmic process • interferon-gamma-mediated signaling pathway • negative regulation of telomerase activity • cell aging • positive regulation of telomere maintenance • cellular senescence • regulation of cell adhesion • defense response to virus • intrinsic apoptotic signaling pathway in response to DNA damage • positive regulation of extrinsic apoptotic signaling pathway • activation of cysteine-type endopeptidase activity involved in apoptotic process • transforming growth factor beta receptor signaling pathway • negative regulation of interleukin-1 beta secretion • proteasome-mediated ubiquitin-dependent protein catabolic process • negative regulation of cell proliferation • positive regulation of defense response to virus by host • apoptotic process • response to cytokine • cell fate commitment • negative regulation of translation in response to oxidative stress • regulation of transcription, DNA-templated • common-partner SMAD protein phosphorylation • branching involved in mammary gland duct morphogenesis • extrinsic apoptotic signaling pathway • SMAD protein import into nucleus • positive regulation of fibroblast proliferation • positive regulation of apoptotic signaling pathway • endoplasmic reticulum calcium ion homeostasis • protein sumoylation • transcription, DNA-templated • PML body organization • negative regulation of cell growth • intrinsic apoptotic signaling pathway by p53 class mediator • innate immune response • viral process • response to gamma radiation • response to UV • regulation of calcium ion transport into cytosol • positive regulation of protein localization to chromosome, telomeric region • fibroblast migration • protein targeting • immune system process • protein stabilization • positive regulation of apoptotic process involved in mammary gland involution • circadian regulation of gene expression • regulation of MHC class I biosynthetic process • negative regulation of viral release from host cell • regulation of circadian rhythm • negative regulation of interleukin-1 secretion • negative regulation of transcription, DNA-templated • maintenance of protein location in nucleus • cellular response to interleukin-4 • intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator • response to hypoxia • protein complex assembly • regulation of double-strand break repair • intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress • retinoic acid receptor signaling pathway • cell cycle arrest • negative regulation of angiogenesis • negative regulation of protein ubiquitination involved in ubiquitin-dependent protein catabolic process • entrainment of circadian clock by photoperiod • negative regulation of mitotic cell cycle • positive regulation of MHC class I biosynthetic process • positive regulation of transcription from RNA polymerase II promoter • regulation of signal transduction by p53 class mediator Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	5371	18854
Ensembl	ENSG00000140464	ENSMUSG00000036986
UniProt	P29590	Q60953
RefSeq (mRNA)	NM_033250 NM_002675 NM_033238 NM_033239 NM_033240 NM_033244 NM_033246 NM_033247 NM_033249	NM_008884 NM_178087 NM_001311088
RefSeq (protein)	NP_002666.1 NP_150241.2 NP_150242.1 NP_150243.2 NP_150247.2 NP_150249.1 NP_150250.2 NP_150252.1 NP_150253.2	NP_001298017.1 NP_032910.3 NP_835188.2
Location (UCSC)	Chr 15: 73.99 – 74.05 Mb	Chr 9: 58.22 – 58.25 Mb
PubMed search	[2]	[3]
Wikidata

View/Edit Human

View/Edit Mouse

Promyelocytic leukemia protein (PML) is a tumor suppressor protein that in humans is encoded by the PML gene.

Function

The protein encoded by this gene is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. This phosphoprotein localizes to nuclear bodies (Nuclear dots) where it functions as a transcription factor and tumor suppressor. Its expression is cell-cycle related and it regulates the p53 response to oncogenic signals. The gene is often involved in the translocation with the retinoic acid receptor alpha gene associated with acute promyelocytic leukemia (APL). Extensive alternative splicing of this gene results in several variations of the protein's central and C-terminal regions; all variants encode the same N-terminus. Alternatively spliced transcript variants encoding different isoforms have been identified.^[4]

Interactions

Promyelocytic leukemia protein has been shown to interact with:

• ANKRD2,^[5]
• CREB-binding protein,^[6][7][8]
• Cyclin T1,^[9]
• Death associated protein 6,^{[10][11][12][13]}
• GATA2,^[14]
• HDAC1,^[15][16]
• HDAC3,^[16]
• HHEX,^[17]
• MAPK11,^[18]
• MYB,^[19]
• Mdm2,^{[20][21][22][23]}
• Nerve Growth factor IB,^[24]
• Nuclear receptor co-repressor 1,^[15]
• Nuclear receptor co-repressor 2,^[15][25]
• P53,^[20][26][27]
• RPL11,^[21]
• Retinoblastoma protein,^[28]
• Retinoic acid receptor alpha,^[6]
• SIN3A,^[15]
• SKI protein,^[15]
• STAT3,^[29]
• Serum response factor^[7] and
• Small ubiquitin-related modifier 1,^[30][31]
• Sp1 transcription factor,^[32]
• TOPBP1,^[33]
• Thymine-DNA glycosylase,^[34] and
• Zinc finger and BTB domain-containing protein 16.^[35]

• PER2,^[36]
• BMAL1,^[36]
• CLOCK,^[36]

See also

• RING finger domain

References

1. "Diseases that are genetically associated with PML view/edit references on wikidata".
2. "Human PubMed Reference:".
3. "Mouse PubMed Reference:".
4. "Entrez Gene: PML promyelocytic leukemia".
5. Kojic S, Medeot E, Guccione E, Krmac H, Zara I, Martinelli V, Valle G, Faulkner G (May 2004). "The Ankrd2 protein, a link between the sarcomere and the nucleus in skeletal muscle". J. Mol. Biol. 339 (2): 313–25. doi:10.1016/j.jmb.2004.03.071. PMID 15136035.
6. Zhong S, Delva L, Rachez C, Cenciarelli C, Gandini D, Zhang H, Kalantry S, Freedman LP, Pandolfi PP (Nov 1999). "A RA-dependent, tumour-growth suppressive transcription complex is the target of the PML-RARalpha and T18 oncoproteins". Nat. Genet. 23 (3): 287–95. doi:10.1038/15463. PMID 10610177.
7. Matsuzaki K, Minami T, Tojo M, Honda Y, Saitoh N, Nagahiro S, Saya H, Nakao M (Mar 2003). "PML-nuclear bodies are involved in cellular serum response". Genes Cells. 8 (3): 275–86. doi:10.1046/j.1365-2443.2003.00632.x. PMID 12622724.
8. Doucas V, Tini M, Egan DA, Evans RM (Mar 1999). "Modulation of CREB binding protein function by the promyelocytic (PML) oncoprotein suggests a role for nuclear bodies in hormone signaling". Proc. Natl. Acad. Sci. U.S.A. 96 (6): 2627–32. doi:10.1073/pnas.96.6.2627. PMC 15819. PMID 10077561.
9. Marcello A, Ferrari A, Pellegrini V, Pegoraro G, Lusic M, Beltram F, Giacca M (May 2003). "Recruitment of human cyclin T1 to nuclear bodies through direct interaction with the PML protein". EMBO J. 22 (9): 2156–66. doi:10.1093/emboj/cdg205. PMC 156077. PMID 12727882.
10. Ishov AM, Sotnikov AG, Negorev D, Vladimirova OV, Neff N, Kamitani T, Yeh ET, Strauss JF, Maul GG (Oct 1999). "PML is critical for ND10 formation and recruits the PML-interacting protein daxx to this nuclear structure when modified by SUMO-1". J. Cell Biol. 147 (2): 221–34. doi:10.1083/jcb.147.2.221. PMC 2174231. PMID 10525530.
11. Li H, Leo C, Zhu J, Wu X, O'Neil J, Park EJ, Chen JD (Mar 2000). "Sequestration and inhibition of Daxx-mediated transcriptional repression by PML". Mol. Cell. Biol. 20 (5): 1784–96. doi:10.1128/mcb.20.5.1784-1796.2000. PMC 85360. PMID 10669754.
12. Lehembre F, Müller S, Pandolfi PP, Dejean A (Jan 2001). "Regulation of Pax3 transcriptional activity by SUMO-1-modified PML". Oncogene. 20 (1): 1–9. doi:10.1038/sj.onc.1204063. PMID 11244500.
13. Zhong S, Salomoni P, Ronchetti S, Guo A, Ruggero D, Pandolfi PP (Feb 2000). "Promyelocytic leukemia protein (PML) and Daxx participate in a novel nuclear pathway for apoptosis". J. Exp. Med. 191 (4): 631–40. doi:10.1084/jem.191.4.631. PMC 2195846. PMID 10684855.
14. Tsuzuki S, Towatari M, Saito H, Enver T (Sep 2000). "Potentiation of GATA-2 activity through interactions with the promyelocytic leukemia protein (PML) and the t(15;17)-generated PML-retinoic acid receptor alpha oncoprotein". Mol. Cell. Biol. 20 (17): 6276–86. doi:10.1128/mcb.20.17.6276-6286.2000. PMC 86102. PMID 10938104.
15. Khan MM, Nomura T, Kim H, Kaul SC, Wadhwa R, Shinagawa T, Ichikawa-Iwata E, Zhong S, Pandolfi PP, Ishii S (Jun 2001). "Role of PML and PML-RARalpha in Mad-mediated transcriptional repression". Mol. Cell. 7 (6): 1233–43. doi:10.1016/s1097-2765(01)00257-x. PMID 11430826.
16. Wu WS, Vallian S, Seto E, Yang WM, Edmondson D, Roth S, Chang KS (Apr 2001). "The growth suppressor PML represses transcription by functionally and physically interacting with histone deacetylases". Mol. Cell. Biol. 21 (7): 2259–68. doi:10.1128/MCB.21.7.2259-2268.2001. PMC 86860. PMID 11259576.
17. Topcu Z, Mack DL, Hromas RA, Borden KL (Nov 1999). "The promyelocytic leukemia protein PML interacts with the proline-rich homeodomain protein PRH: a RING may link hematopoiesis and growth control". Oncogene. 18 (50): 7091–100. doi:10.1038/sj.onc.1203201. PMID 10597310.
18. Shin J, Park B, Cho S, Lee S, Kim Y, Lee SO, Cho K, Lee S, Jin BS, Ahn JH, Choi EJ, Ahn K (Sep 2004). "Promyelocytic leukemia is a direct inhibitor of SAPK2/p38 mitogen-activated protein kinase". J. Biol. Chem. 279 (39): 40994–1003. doi:10.1074/jbc.M407369200. PMID 15273249.
19. Dahle Ø, Bakke O, Gabrielsen OS (Jul 2004). "c-Myb associates with PML in nuclear bodies in hematopoietic cells". Exp. Cell Res. 297 (1): 118–26. doi:10.1016/j.yexcr.2004.03.014. PMID 15194430.
20. Kurki S, Latonen L, Laiho M (Oct 2003). "Cellular stress and DNA damage invoke temporally distinct Mdm2, p53 and PML complexes and damage-specific nuclear relocalization". J. Cell. Sci. 116 (Pt 19): 3917–25. doi:10.1242/jcs.00714. PMID 12915590.
21. Bernardi R, Scaglioni PP, Bergmann S, Horn HF, Vousden KH, Pandolfi PP (Jul 2004). "PML regulates p53 stability by sequestering Mdm2 to the nucleolus". Nat. Cell Biol. 6 (7): 665–72. doi:10.1038/ncb1147. PMID 15195100.
22. Zhu H, Wu L, Maki CG (Dec 2003). "MDM2 and promyelocytic leukemia antagonize each other through their direct interaction with p53". J. Biol. Chem. 278 (49): 49286–92. doi:10.1074/jbc.M308302200. PMID 14507915.
23. Wei X, Yu ZK, Ramalingam A, Grossman SR, Yu JH, Bloch DB, Maki CG (Aug 2003). "Physical and functional interactions between PML and MDM2". J. Biol. Chem. 278 (31): 29288–97. doi:10.1074/jbc.M212215200. PMID 12759344.
24. Wu WS, Xu ZX, Ran R, Meng F, Chang KS (May 2002). "Promyelocytic leukemia protein PML inhibits Nur77-mediated transcription through specific functional interactions". Oncogene. 21 (24): 3925–33. doi:10.1038/sj.onc.1205491. PMID 12032831.
25. Hong SH, Yang Z, Privalsky ML (Nov 2001). "Arsenic trioxide is a potent inhibitor of the interaction of SMRT corepressor with Its transcription factor partners, including the PML-retinoic acid receptor alpha oncoprotein found in human acute promyelocytic leukemia". Mol. Cell. Biol. 21 (21): 7172–82. doi:10.1128/MCB.21.21.7172-7182.2001. PMC 99892. PMID 11585900.
26. Fogal V, Gostissa M, Sandy P, Zacchi P, Sternsdorf T, Jensen K, Pandolfi PP, Will H, Schneider C, Del Sal G (Nov 2000). "Regulation of p53 activity in nuclear bodies by a specific PML isoform". EMBO J. 19 (22): 6185–95. doi:10.1093/emboj/19.22.6185. PMC 305840. PMID 11080164.
27. Guo A, Salomoni P, Luo J, Shih A, Zhong S, Gu W, Pandolfi PP (Oct 2000). "The function of PML in p53-dependent apoptosis". Nat. Cell Biol. 2 (10): 730–6. doi:10.1038/35036365. PMID 11025664.
28. Alcalay M, Tomassoni L, Colombo E, Stoldt S, Grignani F, Fagioli M, Szekely L, Helin K, Pelicci PG (Feb 1998). "The promyelocytic leukemia gene product (PML) forms stable complexes with the retinoblastoma protein". Mol. Cell. Biol. 18 (2): 1084–93. doi:10.1128/mcb.18.2.1084. PMC 108821. PMID 9448006.
29. Kawasaki A, Matsumura I, Kataoka Y, Takigawa E, Nakajima K, Kanakura Y (May 2003). "Opposing effects of PML and PML/RAR alpha on STAT3 activity". Blood. 101 (9): 3668–73. doi:10.1182/blood-2002-08-2474. PMID 12506013.
30. Lin DY, Shih HM (Jul 2002). "Essential role of the 58-kDa microspherule protein in the modulation of Daxx-dependent transcriptional repression as revealed by nucleolar sequestration". J. Biol. Chem. 277 (28): 25446–56. doi:10.1074/jbc.M200633200. PMID 11948183.
31. Kamitani T, Nguyen HP, Kito K, Fukuda-Kamitani T, Yeh ET (Feb 1998). "Covalent modification of PML by the sentrin family of ubiquitin-like proteins". J. Biol. Chem. 273 (6): 3117–20. doi:10.1074/jbc.273.6.3117. PMID 9452416.
32. Vallian S, Chin KV, Chang KS (Dec 1998). "The promyelocytic leukemia protein interacts with Sp1 and inhibits its transactivation of the epidermal growth factor receptor promoter". Mol. Cell. Biol. 18 (12): 7147–56. PMC 109296. PMID 9819401.
33. Xu ZX, Timanova-Atanasova A, Zhao RX, Chang KS (Jun 2003). "PML colocalizes with and stabilizes the DNA damage response protein TopBP1". Mol. Cell. Biol. 23 (12): 4247–56. doi:10.1128/mcb.23.12.4247-4256.2003. PMC 156140. PMID 12773567.
34. Takahashi H, Hatakeyama S, Saitoh H, Nakayama KI (Feb 2005). "Noncovalent SUMO-1 binding activity of thymine DNA glycosylase (TDG) is required for its SUMO-1 modification and colocalization with the promyelocytic leukemia protein". J. Biol. Chem. 280 (7): 5611–21. doi:10.1074/jbc.M408130200. PMID 15569683.
35. Koken MH, Reid A, Quignon F, Chelbi-Alix MK, Davies JM, Kabarowski JH, Zhu J, Dong S, Chen S, Chen Z, Tan CC, Licht J, Waxman S, de Thé H, Zelent A (Sep 1997). "Leukemia-associated retinoic acid receptor alpha fusion partners, PML and PLZF, heterodimerize and colocalize to nuclear bodies". Proc. Natl. Acad. Sci. U.S.A. 94 (19): 10255–60. doi:10.1073/pnas.94.19.10255. PMC 23349. PMID 9294197.
36. Miki T, Zhao Z, Lee CC (2016). "Interactive Organization of the Circadian Core Regulators PER2, BMAL1, CLOCK and PML". Sci Rep. 6: 29174. doi:10.1038/srep29174. PMC 4935866. PMID 27383066.

Further reading

• Zhong S, Salomoni P, Pandolfi PP (2000). "The transcriptional role of PML and the nuclear body". Nat. Cell Biol. 2 (5): E85–90. doi:10.1038/35010583. PMID 10806494.
• Jensen K, Shiels C, Freemont PS (2001). "PML protein isoforms and the RBCC/TRIM motif". Oncogene. 20 (49): 7223–33. doi:10.1038/sj.onc.1204765. PMID 11704850.
• Pearson M, Pelicci PG (2001). "PML interaction with p53 and its role in apoptosis and replicative senescence". Oncogene. 20 (49): 7250–6. doi:10.1038/sj.onc.1204856. PMID 11704853.
• Salomoni P, Pandolfi PP (2002). "The role of PML in tumor suppression". Cell. 108 (2): 165–70. doi:10.1016/S0092-8674(02)00626-8. PMID 11832207.
• Combes R, Balls M, Bansil L, Barratt M, Bell D, Botham P, Broadhead C, Clothier R, George E, Fentem J, Jackson M, Indans I, Loizu G, Navaratnam V, Pentreath V, Phillips B, Stemplewski H, Stewart J (2002). "An assessment of progress in the use of alternatives in toxicity testing since the publication of the report of the second FRAME Toxicity Committee (1991)". Alternatives to laboratory animals : ATLA. 30 (4): 365–406. PMID 12234245.
• Bernardi R, Pandolfi PP (2004). "Role of PML and the PML-nuclear body in the control of programmed cell death". Oncogene. 22 (56): 9048–57. doi:10.1038/sj.onc.1207106. PMID 14663483.
• Beez S, Demmer P, Puccetti E (2012). "Targeting the Acute Promyelocytic Leukemia-Associated Fusion Proteins PML/RARα and PLZF/RARα with Interfering Peptides". PLOS ONE. 7 (11): e48636. doi:10.1371/journal.pone.0048636. PMC 3494703. PMID 23152790.

External links

• PML protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)