AFF4

Summary

Gene Symbol: AFF4
Description: AF4/FMR2 family member 4
Alias: AF5Q31, CHOPS, MCEF, AF4/FMR2 family member 4, ALL1-fused gene from chromosome 5q31 protein, major CDK9 elongation factor-associated protein
Species: human
Products:     AFF4

Top Publications

  1. Taki T, Kano H, Taniwaki M, Sako M, Yanagisawa M, Hayashi Y. AF5q31, a newly identified AF4-related gene, is fused to MLL in infant acute lymphoblastic leukemia with ins(5;11)(q31;q13q23). Proc Natl Acad Sci U S A. 1999;96:14535-40 pubmed
    ..We analyzed an infant early preB ALL with ins(5;11)(q31;q13q23) and identified the AF5q31 gene on chromosome 5q31 as a fusion partner of the MLL gene...
  2. Estable M, Naghavi M, Kato H, Xiao H, Qin J, Vahlne A, et al. MCEF, the newest member of the AF4 family of transcription factors involved in leukemia, is a positive transcription elongation factor-b-associated protein. J Biomed Sci. 2002;9:234-45 pubmed
    ..of cyclin T (including T(1), T(2A) and T(2B)), HSP90 and CDC37, this analysis identified a novel protein named MCEF. Cloning of its cognate cDNA revealed that MCEF is the newest member of the AF4 family of transcription factors ..
  3. Li Z, Guo J, Wu Y, Zhou Q. The BET bromodomain inhibitor JQ1 activates HIV latency through antagonizing Brd4 inhibition of Tat-transactivation. Nucleic Acids Res. 2013;41:277-87 pubmed publisher
  4. Hillman M, Gecz J. Fragile XE-associated familial mental retardation protein 2 (FMR2) acts as a potent transcription activator. J Hum Genet. 2001;46:251-9 pubmed
    ..FMR2 is a member of a family of four proteins, AF4, LAF4, FMR2, and AF5q31. The proteins associated with this family localize to the cell nucleus...
  5. Lu H, Li Z, Xue Y, Schulze Gahmen U, Johnson J, Krogan N, et al. AFF1 is a ubiquitous P-TEFb partner to enable Tat extraction of P-TEFb from 7SK snRNP and formation of SECs for HIV transactivation. Proc Natl Acad Sci U S A. 2014;111:E15-24 pubmed publisher
    ..Our data identify AFF1 as a ubiquitous P-TEFb partner and demonstrate that full Tat transactivation requires the complete SEC. ..
  6. Schulze Gahmen U, Upton H, Birnberg A, Bao K, Chou S, Krogan N, et al. The AFF4 scaffold binds human P-TEFb adjacent to HIV Tat. elife. 2013;2:e00327 pubmed publisher
    ..Tat protein selectively recruits P-TEFb as part of a super elongation complex (SEC) organized on a flexible AFF1 or AFF4 scaffold...
  7. Liu M, Hsu J, Chan C, Li Z, Zhou Q. The ubiquitin ligase Siah1 controls ELL2 stability and formation of super elongation complexes to modulate gene transcription. Mol Cell. 2012;46:325-34 pubmed publisher
    ..SECs) contain two different transcription elongation factors, P-TEFb and ELL1/2, linked by the scaffolding protein AFF4 or AFF1...
  8. He N, Chan C, Sobhian B, Chou S, Xue Y, Liu M, et al. Human Polymerase-Associated Factor complex (PAFc) connects the Super Elongation Complex (SEC) to RNA polymerase II on chromatin. Proc Natl Acad Sci U S A. 2011;108:E636-45 pubmed publisher
    The Super Elongation Complex (SEC), containing transcription elongation activators/coactivators P-TEFb, ELL2, AFF4/1, ENL, and AF9, is recruited by HIV-1 Tat and mixed lineage leukemia (MLL) proteins to activate the expression of HIV-1 ..
  9. Sobhian B, Laguette N, Yatim A, Nakamura M, Levy Y, Kiernan R, et al. HIV-1 Tat assembles a multifunctional transcription elongation complex and stably associates with the 7SK snRNP. Mol Cell. 2010;38:439-51 pubmed publisher
    ..Tatcom1 consists of the core active P-TEFb, MLL-fusion partners involved in leukemia (AF9, AFF4, AFF1, ENL, and ELL), and PAF1 complex...

More Information

Publications41

  1. He N, Liu M, Hsu J, Xue Y, Chou S, Burlingame A, et al. HIV-1 Tat and host AFF4 recruit two transcription elongation factors into a bifunctional complex for coordinated activation of HIV-1 transcription. Mol Cell. 2010;38:428-38 pubmed publisher
    ..Using a sequential affinity-purification scheme, we have identified human transcription factors/coactivators AFF4, ENL, AF9, and elongation factor ELL2 as components of the Tat-P-TEFb complex...
  2. Chou S, Upton H, Bao K, Schulze Gahmen U, Samelson A, He N, et al. HIV-1 Tat recruits transcription elongation factors dispersed along a flexible AFF4 scaffold. Proc Natl Acad Sci U S A. 2013;110:E123-31 pubmed publisher
    ..protein stimulates viral gene expression by recruiting human transcription elongation complexes containing P-TEFb, AFF4, ELL2, and ENL or AF9 to the viral promoter, but the molecular organization of these complexes remains unknown...
  3. Yokoyama A, Lin M, Naresh A, Kitabayashi I, Cleary M. A higher-order complex containing AF4 and ENL family proteins with P-TEFb facilitates oncogenic and physiologic MLL-dependent transcription. Cancer Cell. 2010;17:198-212 pubmed publisher
    ..Thus, AEP recruitment is an integral part of both physiological and pathological MLL-dependent transcriptional pathways. Bypass of its normal recruitment mechanisms is the strategy most frequently used by MLL oncoproteins. ..
  4. Lin C, Smith E, Takahashi H, Lai K, Martin Brown S, Florens L, et al. AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transcription elongation to leukemia. Mol Cell. 2010;37:429-37 pubmed publisher
    ..We have identified super elongation complex (SEC) associated with all chimeras purified. SEC includes ELL, P-TEFb, AFF4, and several other factors...
  5. Karn J. The molecular biology of HIV latency: breaking and restoring the Tat-dependent transcriptional circuit. Curr Opin HIV AIDS. 2011;6:4-11 pubmed publisher
    ..Alternatively, new inhibitors that block proviral reactivation could be developed. ..
  6. Cheng M, Sheng L, Gao Q, Xiong Q, Zhang H, Wu M, et al. The m6A methyltransferase METTL3 promotes bladder cancer progression via AFF4/NF-κB/MYC signaling network. Oncogene. 2019;: pubmed publisher
    ..AF4/FMR2 family member 4 (AFF4), two key regulators of NF-κB pathway (IKBKB and RELA) and MYC were further identified as direct targets of METTL3-..
  7. Liang K, Smith E, Aoi Y, Stoltz K, Katagi H, Woodfin A, et al. Targeting Processive Transcription Elongation via SEC Disruption for MYC-Induced Cancer Therapy. Cell. 2018;175:766-779.e17 pubmed publisher
    ..compounds, KL-1 and its structural homolog KL-2, which disrupt the interaction between the SEC scaffolding protein AFF4 and P-TEFb, resulting in impaired release of Pol II from promoter-proximal pause sites and a reduced average rate ..
  8. Chen X, Zhang J, Luo J, Wu S, Yuan G, Ma N, et al. CSTF2-Induced Shortening of the RAC1 3'UTR Promotes the Pathogenesis of Urothelial Carcinoma of the Bladder. Cancer Res. 2018;78:5848-5862 pubmed publisher
    ..at proximal polyadenylation site of RAC1 attenuated the recruitment of two transcription factors AFF1 and AFF4, causing the defects in elongation...
  9. Nadarajan V, Phan C, Ang C, Liang K, Gan G, Bee P, et al. Identification of copy number alterations by array comparative genomic hybridization in patients with late chronic or accelerated phase chronic myeloid leukemia treated with imatinib mesylate. Int J Hematol. 2011;93:465-473 pubmed publisher
    ..in individual patients, involving regions containing known leukemia-associated genes; CDKN2A/2B, IKZF1, RB1, TLX1, AFF4. CML patients in late stages of their disease, harbor pre-existing and evolving sub-microscopic CNAs that may ..
  10. Qi S, Li Z, Schulze Gahmen U, Stjepanovic G, Zhou Q, Hurley J. Structural basis for ELL2 and AFF4 activation of HIV-1 proviral transcription. Nat Commun. 2017;8:14076 pubmed publisher
    ..0-Å resolution crystal structure of the human ELL2 C-terminal domain bound to its 50-residue binding site on AFF4, the ELLBow. The ELL2 domain has the same arch-shaped fold as the tight junction protein occludin...
  11. Wang Z, Lim B. Mixed cellulose ester filter as a separator for air-diffusion cathode microbial fuel cells. Environ Technol. 2017;38:979-984 pubmed publisher
    ..Mixed cellulose ester filter (MCEF) was examined as a separator for an air-cathode MFC in the present study...
  12. Devinyak O, Havrylyuk D, Zimenkovsky B, Lesyk R. Computational Search for Possible Mechanisms of 4-Thiazolidinones Anticancer Activity: The Power of Visualization. Mol Inform. 2014;33:216-29 pubmed publisher
    ..puromycin and CBU-028 and their pattern is also highly correlated with fraction of methylated CpG sites in CD34, AF5q31 and SYK...
  13. Chen Y, Zhang L, Estarás C, Choi S, Moreno L, Karn J, et al. A gene-specific role for the Ssu72 RNAPII CTD phosphatase in HIV-1 Tat transactivation. Genes Dev. 2014;28:2261-75 pubmed publisher
    ..Chromatin immunoprecipitation (ChIP) experiments reveal that Ssu72, like P-TEFb and AFF4, is recruited by Tat to the integrated HIV-1 proviral promoter in TNF-α signaling 2D10 T cells and leaves the ..
  14. Li Z, Lu H, Zhou Q. A Minor Subset of Super Elongation Complexes Plays a Predominant Role in Reversing HIV-1 Latency. Mol Cell Biol. 2016;36:1194-205 pubmed publisher
    ..Here, we used the CRISPR-Cas9 genome-editing tool to knock out the gene encoding the SEC subunit ELL2, AFF1, or AFF4 in Jurkat/2D10 cells, a well-characterized HIV-1 latency model...
  15. Ui A, Nagaura Y, Yasui A. Transcriptional elongation factor ENL phosphorylated by ATM recruits polycomb and switches off transcription for DSB repair. Mol Cell. 2015;58:468-82 pubmed publisher
    ..Our data suggest that ATM-dependent phosphorylation of ENL functions as switch from elongation to Polycomb-mediated repression to preserve genome integrity. ..
  16. Monroe S, Jo S, Sanders D, Basrur V, Elenitoba Johnson K, Slany R, et al. MLL-AF9 and MLL-ENL alter the dynamic association of transcriptional regulators with genes critical for leukemia. Exp Hematol. 2011;39:77-86.e1-5 pubmed publisher
    ..acid C-terminal domain of AF9 associates with many other MLL translocation partners including Enl, Af4, Laf4, Af5q31, Ell, and Af10...
  17. Colin L, Verdin E, Van Lint C. HIV-1 chromatin, transcription, and the regulatory protein Tat. Methods Mol Biol. 2014;1087:85-101 pubmed publisher
  18. Niedzielski M, Hopewell R, Ismail Z, Estable M. MCEF is localized to the nucleus by protein sequences encoded within three distinct exons, where it represses HIV-1 Tat-transactivation of LTR-directed transcription. Int J Biol Sci. 2007;3:225-36 pubmed
    ..We then examined the structure/function of the most recently discovered AFF member, MCEF (also known as AF5q31 or AFF4)...
  19. Melko M, Douguet D, Bensaid M, Zongaro S, Verheggen C, Gecz J, et al. Functional characterization of the AFF (AF4/FMR2) family of RNA-binding proteins: insights into the molecular pathology of FRAXE intellectual disability. Hum Mol Genet. 2011;20:1873-85 pubmed publisher
    The AFF (AF4/FMR2) family of genes includes four members: AFF1/AF4, AFF2/FMR2, AFF3/LAF4 and AFF4/AF5q31. AFF2/FMR2 is silenced in FRAXE intellectual disability, while the other three members have been reported to form fusion genes as a ..
  20. Mbonye U, Karn J. Transcriptional control of HIV latency: cellular signaling pathways, epigenetics, happenstance and the hope for a cure. Virology. 2014;454-455:328-39 pubmed publisher
    ..An in-depth comprehensive understanding of the molecular control of HIV-1 transcription should inform the development of optimal combinatorial reactivation strategies that are intended to purge the latent viral reservoir...
  21. Li Y, Wen H, Xi Y, Tanaka K, Wang H, Peng D, et al. AF9 YEATS domain links histone acetylation to DOT1L-mediated H3K79 methylation. Cell. 2014;159:558-71 pubmed publisher
    ..Together, our studies identified the evolutionarily conserved YEATS domain as a novel acetyllysine-binding module and established a direct link between histone acetylation and DOT1L-mediated H3K79 methylation in transcription control. ..
  22. Taube R, Peterlin M. Lost in transcription: molecular mechanisms that control HIV latency. Viruses. 2013;5:902-27 pubmed publisher
  23. Schulze Gahmen U, Echeverria I, Stjepanovic G, Bai Y, Lu H, Schneidman Duhovny D, et al. Insights into HIV-1 proviral transcription from integrative structure and dynamics of the Tat:AFF4:P-TEFb:TAR complex. elife. 2016;5: pubmed publisher
    ..Here we report the 5.9 Å structure of HIV-1 TAR in complex with HIV-1 Tat and human AFF4, CDK9, and CycT1...
  24. Zhou C, Xiong Q, Zhu X, Du W, Deng P, Li X, et al. AFF1 and AFF4 differentially regulate the osteogenic differentiation of human MSCs. Bone Res. 2017;5:17044 pubmed publisher
    AFF1 and AFF4 belong to the AFF (AF4/FMR2) family of proteins, which function as scaffolding proteins linking two different transcription elongation factors, positive elongation factor b (P-TEFb) and ELL1/2, in super elongation complexes (..
  25. Gu J, Babayeva N, Suwa Y, Baranovskiy A, Price D, Tahirov T. Crystal structure of HIV-1 Tat complexed with human P-TEFb and AFF4. Cell Cycle. 2014;13:1788-97 pubmed publisher
    ..Tat•P-TEFb into the SEC is critical for HIV transcription, we have determined the crystal structure of the Tat•AFF4•P-TEFb complex containing HIV-1 Tat (residues 1-48), human Cyclin T1 (1-266), human Cdk9 (7-332), and human AFF4 (..
  26. Schulze Gahmen U, Lu H, Zhou Q, Alber T. AFF4 binding to Tat-P-TEFb indirectly stimulates TAR recognition of super elongation complexes at the HIV promoter. elife. 2014;3:e02375 pubmed publisher
    ..and TAR, we determined the crystal structure of a quaternary complex containing Tat, P-TEFb, and the SEC scaffold, AFF4. Tat and AFF4 fold on the surface of CycT1 and interact directly...
  27. Izumi K, Nakato R, Zhang Z, Edmondson A, Noon S, Dulik M, et al. Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin. Nat Genet. 2015;47:338-44 pubmed publisher
    ..probands with a new syndrome that phenotypically overlaps Cornelia de Lange syndrome (CdLS) that we have named CHOPS syndrome (C for cognitive impairment and coarse facies, H for heart defects, O for obesity, P for pulmonary ..
  28. Lu H, Li Z, Zhang W, Schulze Gahmen U, Xue Y, Zhou Q. Gene target specificity of the Super Elongation Complex (SEC) family: how HIV-1 Tat employs selected SEC members to activate viral transcription. Nucleic Acids Res. 2015;43:5868-79 pubmed publisher
    The AF4/FMR2 proteins AFF1 and AFF4 act as a scaffold to assemble the Super Elongation Complex (SEC) that strongly activates transcriptional elongation of HIV-1 and cellular genes...
  29. Zeisig D, Bittner C, Zeisig B, Garcia Cuellar M, Hess J, Slany R. The eleven-nineteen-leukemia protein ENL connects nuclear MLL fusion partners with chromatin. Oncogene. 2005;24:5525-32 pubmed
    ..In two-hybrid studies, ENL interacted with AF4 and AF5q31 as well as with a fragment of AF10...
  30. Karn J, Stoltzfus C. Transcriptional and posttranscriptional regulation of HIV-1 gene expression. Cold Spring Harb Perspect Med. 2012;2:a006916 pubmed publisher
    ..In cells that are not fully activated, limiting levels of Tat and Rev act as potent blocks to premature virus production. ..
  31. Tan J, Jones M, Koseki H, Nakayama M, Muntean A, Maillard I, et al. CBX8, a polycomb group protein, is essential for MLL-AF9-induced leukemogenesis. Cancer Cell. 2011;20:563-75 pubmed publisher
    ..Surprisingly, Cbx8-deficient mice are viable and display no apparent hematopoietic defects. Together, our findings demonstrate that CBX8 plays an essential role in MLL-AF9 transcriptional regulation and leukemogenesis. ..
  32. Nilson K, Price D. The Role of RNA Polymerase II Elongation Control in HIV-1 Gene Expression, Replication, and Latency. Genet Res Int. 2011;2011:726901 pubmed publisher
    ..HIV, the causative agent of AIDS, is a worldwide health concern. It is hoped that knowledge of the mechanisms regulating the expression of the HIV genome will lead to treatments and ultimately a cure. ..