Promyelocytic Leukemia Zinc Finger-retinoic Acid Receptor α (PLZF-RARα), an Oncogenic Transcriptional Repressor of Cyclin-dependent Kinase Inhibitor 1A (p21WAF/CDKN1A) and Tumor Protein P53 (TP53) Genes

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2014 May 14

PMID 24821728

Citations 8

Authors

Won-Il Choi

Jae-Hyeon Yoon

Min-Young Kim

Dong-In Koh

Jonathan D Licht

Kunhong Kim

Man-Wook Hur

Affiliations

Soon will be listed here.

Abstract

Promyelocytic leukemia zinc finger-retinoic acid receptor α (PLZF-RARα) is an oncogene transcriptional repressor that is generated by a chromosomal translocation between the PLZF and RARα genes in acute promyelocytic leukemia (APL-type) patients. The molecular interaction between PLZF-RARα and the histone deacetylase corepressor was proposed to be important in leukemogenesis. We found that PLZF-RARα can repress transcription of the p21WAF/CDKN1A gene, which encodes the negative cell cycle regulator p21 by binding to its proximal promoter Sp1-binding GC-boxes 3, 4, 5/6, a retinoic acid response element (RARE), and distal p53-responsive elements (p53REs). PLZF-RARα also acts as a competitive transcriptional repressor of p53, RARα, and Sp1. PLZF-RARα interacts with co-repressors such as mSin3A, NCoR, and SMRT, thereby deacetylating histones Ac-H3 and Ac-H4 at the CDKN1A promoter. PLZF-RARα also interacts with the MBD3-NuRD complex, leading to epigenetic silencing of CDKN1A through DNA methylation. Furthermore, PLZF-RARα represses TP53 and increases p53 protein degradation by ubiquitination, further repressing p21 expression. Resultantly, PLZF-RARα promotes cell proliferation and significantly increases the number of cells in S-phase.

Citing Articles

Activation of Genes by Nuclear Receptor/Specificity Protein (Sp) Interactions in Cancer.

Safe S, Farkas E, Hailemariam A, Oany A, Sivaram G, Tsui W Cancers (Basel). 2025; 17(2).

PMID: 39858066 PMC: 11763981. DOI: 10.3390/cancers17020284.

BTB protein family and human breast cancer: signaling pathways and clinical progress.

Zhang H, Ouyang C J Cancer Res Clin Oncol. 2023; 149(17):16213-16229.

PMID: 37682360 DOI: 10.1007/s00432-023-05314-9.

p53 as a unique target of action of cisplatin in acute leukaemia cells.

Kumar S, Tchounwou P J Cell Mol Med. 2022; 26(17):4727-4739.

PMID: 35946055 PMC: 9443951. DOI: 10.1111/jcmm.17502.

Occupancy maps of 208 chromatin-associated proteins in one human cell type.

Partridge E, Chhetri S, Prokop J, Ramaker R, Jansen C, Goh S Nature. 2020; 583(7818):720-728.

PMID: 32728244 PMC: 7398277. DOI: 10.1038/s41586-020-2023-4.

BTB/POZ zinc finger protein ZBTB16 inhibits breast cancer proliferation and metastasis through upregulating ZBTB28 and antagonizing BCL6/ZBTB27.

He J, Wu M, Xiong L, Gong Y, Yu R, Peng W Clin Epigenetics. 2020; 12(1):82.

PMID: 32517789 PMC: 7285556. DOI: 10.1186/s13148-020-00867-9.

References

Gartel A, Ye X, Goufman E, Shianov P, Hay N, Najmabadi F . Myc represses the p21(WAF1/CIP1) promoter and interacts with Sp1/Sp3. Proc Natl Acad Sci U S A. 2001; 98(8):4510-5. PMC: 31865. DOI: 10.1073/pnas.081074898. View

Phan R, Dalla-Favera R . The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells. Nature. 2004; 432(7017):635-9. DOI: 10.1038/nature03147. View

Warrell Jr R, de The H, Wang Z, Degos L . Acute promyelocytic leukemia. N Engl J Med. 1993; 329(3):177-89. DOI: 10.1056/NEJM199307153290307. View

Licht J, Shaknovich R, English M, Melnick A, Li J, Reddy J . Reduced and altered DNA-binding and transcriptional properties of the PLZF-retinoic acid receptor-alpha chimera generated in t(11;17)-associated acute promyelocytic leukemia. Oncogene. 1996; 12(2):323-36. View

Rice K, Hormaeche I, Doulatov S, Flatow J, Grimwade D, Mills K . Comprehensive genomic screens identify a role for PLZF-RARalpha as a positive regulator of cell proliferation via direct regulation of c-MYC. Blood. 2009; 114(27):5499-511. PMC: 2798864. DOI: 10.1182/blood-2009-03-206524. View

Maeda T, Merghoub T, Hobbs R, Dong L, Maeda M, Zakrzewski J . Regulation of B versus T lymphoid lineage fate decision by the proto-oncogene LRF. Science. 2007; 316(5826):860-6. PMC: 2978506. DOI: 10.1126/science.1140881. View

Crook J, Dunn N, Colman A . Repressed by a NuRD. Nat Cell Biol. 2006; 8(3):212-4. DOI: 10.1038/ncb0306-212. View

Mangelsdorf D, Ong E, Dyck J, Evans R . Nuclear receptor that identifies a novel retinoic acid response pathway. Nature. 1990; 345(6272):224-9. DOI: 10.1038/345224a0. View

De Matteis S, Nervi C, Tomassoni L, Gelmetti V, Cioce M, Fanelli M . Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukaemia. Nature. 1998; 391(6669):815-8. DOI: 10.1038/35901. View

10.

Heinzel T, Lavinsky R, Mullen T, Soderstrom M, Laherty C, Torchia J . A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression. Nature. 1997; 387(6628):43-8. DOI: 10.1038/387043a0. View

11.

Koutsodontis G, Tentes I, Papakosta P, Moustakas A, Kardassis D . Sp1 plays a critical role in the transcriptional activation of the human cyclin-dependent kinase inhibitor p21(WAF1/Cip1) gene by the p53 tumor suppressor protein. J Biol Chem. 2001; 276(31):29116-25. DOI: 10.1074/jbc.M104130200. View

12.

He L, Guidez F, Tribioli C, Peruzzi D, Ruthardt M, Zelent A . Distinct interactions of PML-RARalpha and PLZF-RARalpha with co-repressors determine differential responses to RA in APL. Nat Genet. 1998; 18(2):126-35. DOI: 10.1038/ng0298-126. View

13.

Lin R, Nagy L, Inoue S, Shao W, Miller Jr W, Evans R . Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature. 1998; 391(6669):811-4. DOI: 10.1038/35895. View

14.

Gartel A, Radhakrishnan S . Lost in transcription: p21 repression, mechanisms, and consequences. Cancer Res. 2005; 65(10):3980-5. DOI: 10.1158/0008-5472.CAN-04-3995. View

15.

Noh E, Jang E, Jeong G, Lee Y, Min C, Lee J . Methyl CpG-binding domain protein 3 mediates cancer-selective cytotoxicity by histone deacetylase inhibitors via differential transcriptional reprogramming in lung cancer cells. Cancer Res. 2005; 65(24):11400-10. DOI: 10.1158/0008-5472.CAN-05-1092. View

16.

Lin R, Sternsdorf T, Tini M, Evans R . Transcriptional regulation in acute promyelocytic leukemia. Oncogene. 2001; 20(49):7204-15. DOI: 10.1038/sj.onc.1204853. View

17.

Villa R, Morey L, Raker V, Buschbeck M, Gutierrez A, De Santis F . The methyl-CpG binding protein MBD1 is required for PML-RARalpha function. Proc Natl Acad Sci U S A. 2006; 103(5):1400-5. PMC: 1360559. DOI: 10.1073/pnas.0509343103. View

18.

Shaknovich R, Yeyati P, Ivins S, Melnick A, Lempert C, Waxman S . The promyelocytic leukemia zinc finger protein affects myeloid cell growth, differentiation, and apoptosis. Mol Cell Biol. 1998; 18(9):5533-45. PMC: 109138. DOI: 10.1128/MCB.18.9.5533. View

19.

Kardassis D, Papakosta P, Pardali K, Moustakas A . c-Jun transactivates the promoter of the human p21(WAF1/Cip1) gene by acting as a superactivator of the ubiquitous transcription factor Sp1. J Biol Chem. 1999; 274(41):29572-81. DOI: 10.1074/jbc.274.41.29572. View

20.

He L, Tolentino T, Grayson P, Zhong S, Warrell Jr R, Rifkind R . Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia. J Clin Invest. 2001; 108(9):1321-30. PMC: 209432. DOI: 10.1172/JCI11537. View