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No annotation is available in this section for this article. The content below is taken from a related TF, ZBTB16 (Homo sapiens).
  1. (2006) Kelly KF, Daniel JM. POZ for effect--POZ-ZF transcription factors in cancer and development. Trends Cell Biol., 16(11):578-87.
    The BTB/POZ-ZF [Broad complex, Tramtrack, Bric à brac (BTB) or poxvirus and zinc finger (POZ)-zinc finger] protein family comprises a diverse group of transcription factors. POZ-ZF proteins have been implicated in many biological processes, including B cell fate determination, DNA damage responses, cell cycle progression and a multitude of developmental events, including gastrulation, limb formation and hematopoietic stem cell fate determination. Consequently, dysfunction of vertebrate POZ-ZF proteins, such as promyelocytic leukemia zinc finger (PLZF), B cell lymphoma 6 (Bcl-6), hypermethylated in cancer 1 (HIC-1), Kaiso, ZBTB7 and Fanconi anemia zinc finger (FAZF), has been linked directly or indirectly to tumorigenesis and developmental disorders. Here, we discuss recent advances in the POZ-ZF field and the implications for the design of future studies to elucidate the biological roles of these unique transcription factors.
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  2. (2000) Barna M, Hawe N, Niswander L, Pandolfi PP. Plzf regulates limb and axial skeletal patterning. Nat. Genet., 25(2):166-72.
    The promyelocytic leukaemia zinc finger (Plzf) protein (encoded by the gene Zfp145) belongs to the POZ/zinc-finger family of transcription factors. Here we generate Zfp145-/- mice and show that Plzf is essential for patterning of the limb and axial skeleton. Plzf inactivation results in patterning defects affecting all skeletal structures of the limb, including homeotic transformations of anterior skeletal elements into posterior structures. We demonstrate that Plzf acts as a growth-inhibitory and pro-apoptotic factor in the limb bud. The expression of members of the abdominal b (Abdb) Hox gene complex, as well as genes encoding bone morphogenetic proteins (Bmps), is altered in the developing limb of Zfp145-/- mice. Plzf regulates the expression of these genes in the absence of aberrant polarizing activity and independently of known patterning genes. Zfp145-/- mice also exhibit anterior-directed homeotic transformation throughout the axial skeleton with associated alterations in Hox gene expression. Plzf is therefore a mediator of anterior-to-posterior (AP) patterning in both the axial and appendicular skeleton and acts as a regulator of Hox gene expression.
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  3. (1997) Hong SH, David G, Wong CW, Dejean A, Privalsky ML. SMRT corepressor interacts with PLZF and with the PML-retinoic acid receptor alpha (RARalpha) and PLZF-RARalpha oncoproteins associated with acute promyelocytic leukemia. Proc. Natl. Acad. Sci. U.S.A., 94(17):9028-33.
    Retinoic acid receptors (RARs) are hormone-regulated transcription factors that control key aspects of normal differentiation. Aberrant RAR activity may be a causal factor in neoplasia. Human acute promyelocytic leukemia, for example, is tightly linked to chromosomal translocations that fuse novel amino acid sequences (denoted PML, PLZF, and NPM) to the DNA-binding and hormone-binding domains of RARalpha. The resulting chimeric receptors have unique transcriptional properties that may contribute to leukemogenesis. Normal RARs repress gene transcription by associating with ancillary factors denoted corepressors (also referred to as SMRT, N-CoR, TRAC, or RIP13). We report here that the PML-RARalpha and PLZF-RARalpha oncoproteins retain the ability of RARalpha to associate with corepressors, and that this corepressor association correlates with certain aspects of the leukemic phenotype. Unexpectedly, the PLZF moiety itself can interact with SMRT corepressor. This interaction with corepressor is mediated, in part, by a POZ motif within PLZF. Given the presence of POZ motifs in a number of known transcriptional repressors, similar interactions with SMRT may play a role in transcriptional silencing by a variety of both receptor and nonreceptor transcription factors.
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    Seth Frietze (sfrietze@ucdavis.edu) on August 12, 2008 wrote:
     This is the first article describing an interaction between wild-type PLZF and transcriptional corepressors. 
  4. (2008) Felicetti F, Errico MC, Bottero L, Segnalini P, Stoppacciaro A, Biffoni M, Felli N, Mattia G, Petrini M, Colombo MP, Peschle C, Carè A. The promyelocytic leukemia zinc finger-microRNA-221/-222 pathway controls melanoma progression through multiple oncogenic mechanisms. Cancer Res., 68(8):2745-54.
    The incidence of cutaneous melanoma is steadily increasing. Although several molecular abnormalities have been associated with melanoma progression, the mechanisms underlying the differential gene expression are still largely unknown and targeted therapies are not yet available. Noncoding small RNAs, termed microRNAs (miR), have been recently reported to play important roles in major cellular processes, including those involved in cancer development and progression. We have identified the promyelocytic leukemia zinc finger (PLZF) transcription factor as a repressor of miR-221 and miR-222 by direct binding to their putative regulatory region. Specifically, PLZF silencing in melanomas unblocks miR-221 and miR-222, which in turn controls the progression of the neoplasia through down-modulation of p27Kip1/CDKN1B and c-KIT receptor, leading to enhanced proliferation and differentiation blockade of the melanoma cells, respectively. In vitro and in vivo functional studies, including the use of antisense "antagomir" oligonucleotides, confirmed the key role of miR-221/-222 in regulating the progression of human melanoma; this suggests that targeted therapies suppressing miR-221/-222 may prove beneficial in advanced melanoma.
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  5. (2008) Petrie K, Guidez F, Zhu J, Howell L, Owen G, Chew YP, Parks S, Waxman S, Licht J, Mittnacht S, Zelent A. Retinoblastoma protein and the leukemia-associated PLZF transcription factor interact to repress target gene promoters. Oncogene, 27(39):5260-6.
    Translocations of the retinoic acid receptor-alpha (RARalpha) locus with the promyelocytic leukemia zinc-finger (PLZF) or PML genes lead to expression of oncogenic PLZF-RARalpha or PML-RARalpha fusion proteins, respectively. These fusion oncoproteins constitutively repress RARalpha target genes, in large part through aberrant recruitment of multiprotein co-repressor complexes. PML and PML-RARalpha have previously been shown to associate with the retinoblastoma (Rb) tumour suppressor protein in its hypophosphorylated state. Here, we demonstrate that PLZF also interacts with Rb in vitro and in vivo. The interaction between PLZF and Rb is mediated through the Rb pocket and the region of PLZF that lies between its transcriptional repression (poxvirus and zinc-finger, POZ) and DNA-binding (zinc-finger) domains. In addition, Rb can simultaneously interact with PLZF and the E2F1 S phase-inducing transcription factor, suggesting that these proteins can exist in the same multiprotein complex. In contrast to the interaction of Rb with PML or E2F1, the PLZF-Rb interaction is not dependent on hypophosphorylation of Rb. These data are supported by chromatin immunoprecipitation analysis, which indicates that PLZF associates with the promoter region of CDC6, a known E2F/Rb target gene. Co-expression of PLZF and Rb results in enhancement of transcriptional repression of PLZF and E2F/Rb target genes, indicating functional co-operation between the two proteins. Both PLZF and Rb have been shown to function in stem cells and taken together these data suggest that interactions between PLZF and Rb could be important in stem cell biology.
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  6. (2008) Labbaye C, Spinello I, Quaranta MT, Pelosi E, Pasquini L, Petrucci E, Biffoni M, Nuzzolo ER, Billi M, Foà R, Brunetti E, Grignani F, Testa U, Peschle C. A three-step pathway comprising PLZF/miR-146a/CXCR4 controls megakaryopoiesis. Nat. Cell Biol., 10(7):788-801.
    MicroRNAs (miRNAs or miRs) regulate diverse normal and abnormal cell functions. We have identified a regulatory pathway in normal megakaryopoiesis, involving the PLZF transcription factor, miR-146a and the SDF-1 receptor CXCR4. In leukaemic cell lines PLZF overexpression downmodulated miR-146a and upregulated CXCR4 protein, whereas PLZF knockdown induced the opposite effects. In vitro assays showed that PLZF interacts with and inhibits the miR-146a promoter, and that miR-146a targets CXCR4 mRNA, impeding its translation. In megakaryopoietic cultures of CD34(+) progenitors, PLZF was upregulated, whereas miR-146a expression decreased and CXCR4 protein increased. MiR-146a overexpression and PLZF or CXCR4 silencing impaired megakaryocytic (Mk) proliferation, differentiation and maturation, as well as Mk colony formation. Mir-146a knockdown induced the opposite effects. Rescue experiments indicated that the effects of PLZF and miR-146a are mediated by miR-146a and CXCR4, respectively. Our data indicate that megakaryopoiesis is controlled by a cascade pathway, in which PLZF suppresses miR-146a transcription and thereby activates CXCR4 translation.
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  7. (2008) Kovalovsky D, Uche OU, Eladad S, Hobbs RM, Yi W, Alonzo E, Chua K, Eidson M, Kim HJ, Im JS, Pandolfi PP, Sant'Angelo DB. The BTB-zinc finger transcriptional regulator PLZF controls the development of invariant natural killer T cell effector functions. Nat. Immunol., 9(9):1055-64.
    Invariant natural killer T cells (iNKT cells) have an innate immunity-like rapidity of response and the ability to modulate the effector functions of other cells. We show here that iNKT cells specifically expressed the BTB-zinc finger transcriptional regulator PLZF. In the absence of PLZF, iNKT cells developed, but they lacked many features of innate T cells. PLZF-deficient iNKT cells accumulated in lymph nodes rather than in the liver, did not express NK markers and did not have the characteristic activated phenotype. PLZF-deficient iNKT cells failed to secrete large amounts of interleukin 4 and interferon-gamma after activation; however, some cells produced either interleukin 4 or interferon-gamma but not both. PLZF, therefore, is an iNKT cell-specific transcription factor that is necessary for full functionality.
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  8. (2005) Barna M, Pandolfi PP, Niswander L. Gli3 and Plzf cooperate in proximal limb patterning at early stages of limb development. Nature, 436(7048):277-81.
    The vertebrate limb initially develops as a bud of mesenchymal cells that subsequently aggregate in a proximal to distal (P-D) sequence to give rise to cartilage condensations that prefigure all limb skeletal components. Of the three cardinal limb axes, the mechanisms that lead to establishment and patterning of skeletal elements along the P-D axis are the least understood. Here we identify a genetic interaction between Gli3 (GLI-Kruppel family member 3) and Plzf (promyelocytic leukaemia zinc finger, also known as Zbtb16 and Zfp145), which is required specifically at very early stages of limb development for all proximal cartilage condensations in the hindlimb (femur, tibia, fibula). Notably, distal condensations comprising the foot are relatively unperturbed in Gli3(-/-);Plzf(-/-) mouse embryos. We demonstrate that the cooperative activity of Gli3 and Plzf establishes the correct temporal and spatial distribution of chondrocyte progenitors in the proximal limb-bud independently of known P-D patterning markers and overall limb-bud size. Moreover, the limb defects in Gli3(-/-);Plzf(-/-) embryos correlate with the transient death of a specific subset of proximal mesenchymal cells that express bone morphogenetic protein receptor, type 1B (Bmpr1b) at the onset of limb development. These findings suggest that the development of proximal and distal skeletal elements is distinctly regulated early during limb-bud formation. The initial division of the vertebrate limb into two distinct molecular domains is consistent with fossil evidence indicating that the upper and lower extremities of the limb have different evolutionary origins.
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  9. (2004) Costoya JA, Hobbs RM, Barna M, Cattoretti G, Manova K, Sukhwani M, Orwig KE, Wolgemuth DJ, Pandolfi PP. Essential role of Plzf in maintenance of spermatogonial stem cells. Nat. Genet., 36(6):653-9.
    Little is known of the molecular mechanisms whereby spermatogonia, mitotic germ cells of the testis, self-renew and differentiate into sperm. Here we show that Zfp145, encoding the transcriptional repressor Plzf, has a crucial role in spermatogenesis. Zfp145 expression was restricted to gonocytes and undifferentiated spermatogonia and was absent in tubules of W/W(v) mutants that lack these cells. Mice lacking Zfp145 underwent a progressive loss of spermatogonia with age, associated with increases in apoptosis and subsequent loss of tubule structure but without overt differentiation defects or loss of the supporting Sertoli cells. Spermatogonial transplantation experiments revealed a depletion of spermatogonial stem cells in the adult. Microarray analysis of isolated spermatogonia from Zfp145-null mice before testis degeneration showed alterations in the expression profile of genes associated with spermatogenesis. These results identify Plzf as a spermatogonia-specific transcription factor in the testis that is required to regulate self-renewal and maintenance of the stem cell pool.
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  10. (2004) Buaas FW, Kirsh AL, Sharma M, McLean DJ, Morris JL, Griswold MD, de Rooij DG, Braun RE. Plzf is required in adult male germ cells for stem cell self-renewal. Nat. Genet., 36(6):647-52.
    Adult germline stem cells are capable of self-renewal, tissue regeneration and production of large numbers of differentiated progeny. We show here that the classical mouse mutant luxoid affects adult germline stem cell self-renewal. Young homozygous luxoid mutant mice produce limited numbers of normal spermatozoa and then progressively lose their germ line after birth. Transplantation studies showed that germ cells from mutant mice did not colonize recipient testes, suggesting that the defect is intrinsic to the stem cells. We determined that the luxoid mutant contains a nonsense mutation in the gene encoding Plzf, a transcriptional repressor that regulates the epigenetic state of undifferentiated cells, and showed that Plzf is coexpressed with Oct4 in undifferentiated spermatogonia. This is the first gene shown to be required in germ cells for stem cell self-renewal in mammals.
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  11. (2002) Barna M, Merghoub T, Costoya JA, Ruggero D, Branford M, Bergia A, Samori B, Pandolfi PP. Plzf mediates transcriptional repression of HoxD gene expression through chromatin remodeling. Dev. Cell, 3(4):499-510.
    The molecular mechanisms that regulate coordinated and colinear activation of Hox gene expression in space and time remain poorly understood. Here we demonstrate that Plzf regulates the spatial expression of the AbdB HoxD gene complex by binding to regulatory elements required for restricted Hox gene expression and can recruit histone deacetylases to these sites. We show by scanning forced microscopy that Plzf, via homodimerization, can form DNA loops and bridge distant Plzf binding sites located within HoxD gene regulatory elements. Furthermore, we demonstrate that Plzf physically interacts with Polycomb proteins on DNA. We propose a model by which the balance between activating morphogenic signals and transcriptional repressors such as Plzf establishes proper Hox gene expression boundaries in the limb bud.
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  12. (1998) David G, Alland L, Hong SH, Wong CW, DePinho RA, Dejean A. Histone deacetylase associated with mSin3A mediates repression by the acute promyelocytic leukemia-associated PLZF protein. Oncogene, 16(19):2549-56.
    The PLZF gene was identified first by its fusion with the retinoic acid receptor alpha gene in the t(11;17) translocation associated with a retinoic acid resistant form of acute promyelocytic leukemia (APL). It encodes a krüppel-like zinc finger protein with a POZ domain shared with a subset of regulatory proteins including the BCL6 leukemogenic protein. PLZF, like BCL6, strongly represses transcription initiated from different promoters. Here we show that PLZF associates in vitro and in vivo with the Mad co-repressor mSin3A and the histone deacetylase HDAC1. Two domains in PLZF and the PAH1 structure of mSin3A mediate these interactions. Trichostatin A, a specific inhibitor of histone deacetylases, significantly reduces PLZF repression. These data strongly suggest that, like nuclear receptors and Mad, PLZF represses transcription by recruiting a histone deacetylase through the SMRT-mSin3-HDAC co-repressor complex. We also show that BCL6 associates with HDAC1 indicating that this type of regulation might be common to POZ/Zinc finger proteins involved in human leukemias. This work supports a role for deregulated histone deacetylation in the development of both lymphoid and myeloid neoplasia in human and suggests that targeted histone deacetylase inhibitors may be useful for treatment of certain types of malignancies.
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  13. (1998) Shaknovich R, Yeyati PL, Ivins S, Melnick A, Lempert C, Waxman S, Zelent A, Licht JD. The promyelocytic leukemia zinc finger protein affects myeloid cell growth, differentiation, and apoptosis. Mol. Cell. Biol., 18(9):5533-45.
    The promyelocytic leukemia zinc finger (PLZF) gene, which is disrupted in therapy-resistant, t(11;17)(q23;q21)-associated acute promyelocytic leukemia (APL), is expressed in immature hematopoietic cells and is down-regulated during differentiation. To determine the role of PLZF in myeloid development, we engineered expression of PLZF in murine 32Dcl3 cells. Expression of PLZF had a dramatic growth-suppressive effect accompanied by accumulation of cells in the G0/G1 compartment of the cell cycle and an increased incidence of apoptosis. PLZF-expressing pools also secreted a growth-inhibitory factor, which could explain the severe growth suppression of PLZF-expressing pools that occurred despite the fact that only half of the cells expressed high levels of PLZF. PLZF overexpression inhibited myeloid differentiation of 32Dcl3 cells in response to granulocyte and granulocyte-macrophage colony-stimulating factors. Furthermore, cells that expressed PLZF appeared immature as demonstrated by morphology, increased expression of Sca-1, and decreased expression of Gr-1. These findings suggest that PLZF is an important regulator of cell growth, death, and differentiation. Disruption of PLZF function associated with t(11;17) may be a critical event leading to APL.
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  14. (1997) Li JY, English MA, Ball HJ, Yeyati PL, Waxman S, Licht JD. Sequence-specific DNA binding and transcriptional regulation by the promyelocytic leukemia zinc finger protein. J. Biol. Chem., 272(36):22447-55.
    Chromosomal translocation t(11;17)(q23;21) is associated with a retinoic acid-resistant form of acute promyelocytic leukemia. The translocation fuses the RARalpha gene to the PLZF gene, resulting in the formation of reciprocal fusion proteins, hypothesized to play prominent roles in leukemogenesis. Promyelocytic leukemia zinc finger (PLZF) encodes a transcription factor with nine Krüppel-like zinc fingers, seven of which are retained in the t(11;17) fusion protein RARalpha-PLZF. We identified a specific DNA-binding site for the PLZF protein and showed that PLZF binds to this site through its most carboxyl seven zinc fingers. In co-transfection experiments, PLZF repressed transcription through its cognate binding site. This repression function of PLZF was mapped to two regions on the protein, including the evolutionarily conserved POZ domain. In contrast, the RARalpha-PLZF protein activated transcription of a promoter containing a PLZF response element. These results suggest that RARalpha-PLZF, generated in acute promyelocytic leukemia, is an aberrant transcription factor that can deregulate the expression of PLZF target genes and contribute to leukemogenesis.
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  15. (2009) Xu D, Holko M, Sadler AJ, Scott B, Higashiyama S, Berkofsky-Fessler W, McConnell MJ, Pandolfi PP, Licht JD, Williams BR. Promyelocytic leukemia zinc finger protein regulates interferon-mediated innate immunity. Immunity, 30(6):802-16.
    Interferons (IFNs) direct innate and acquired immune responses and, accordingly, are used therapeutically to treat a number of diseases, yet the diverse effects they elicit are not fully understood. Here, we identified the promyelocytic leukemia zinc finger (PLZF) protein as a previously unrecognized component of the IFN response. IFN stimulated an association of PLZF with promyelocytic leukemia protein (PML) and histone deacetylase 1 (HDAC1) to induce a decisive subset of IFN-stimulated genes (ISGs). Consequently, PLZF-deficient mice had a specific ISG expression defect and as a result were more susceptible to viral infection. This susceptibility correlated with a marked decrease in the expression of the key antiviral mediators and an impaired IFN-mediated induction of natural killer cell function. These results provide new insights into the regulatory mechanisms of IFN signaling and the induction of innate antiviral immunity.
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  16. (2008) Costoya JA, Hobbs RM, Pandolfi PP. Cyclin-dependent kinase antagonizes promyelocytic leukemia zinc-finger through phosphorylation. Oncogene, 27(27):3789-96.
    Acute promyelocytic leukemia is associated with chromosomal translocations that involve the RARalpha gene and several distinct loci producing a variety of fusion proteins. One such fusion partner is promyelocytic leukemia zinc-finger gene (PLZF), a member of the POK (POZ and Krüppel) family of transcriptional repressors that is a key developmental regulator, stem cell maintenance factor and tumor suppressor. Overexpression of PLZF has been shown to induce cell cycle arrest at the G(1) to S transition and repress the expression of key pro-proliferative genes such as CCNA2 and MYC. However, given this data suggesting an important growth inhibitory role for PLZF, relatively little is known regarding regulation of its activity. Here we show that the main cyclin-dependent kinase involved at the G(1) to S transition (CDK2) phosphorylates PLZF at two consensus sites found within PEST domains present in the hinge region of the protein. This phosphorylation triggers the ubiquitination and subsequent degradation of PLZF, which impairs PLZF transcriptional repression ability and antagonizes its growth inhibitory effects. This critical mechanism of PLZF regulation may thus be relevant for cell cycle progression during the development and the pathogenesis of human cancer.
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  17. (2006) Ko JH, Son W, Bae GY, Kang JH, Oh W, Yoo OJ. A new hepatocytic isoform of PLZF lacking the BTB domain interacts with ATP7B, the Wilson disease protein, and positively regulates ERK signal transduction. J. Cell. Biochem., 99(3):719-34.
    The promyelocytic leukemia zinc finger (PLZF) protein has been described as a transcriptional repressor of the BTB-domain/zinc-finger family, and shown to regulate the expression of Hox genes during embryogenesis and the expression of cyclin A in the cell cycle progression. Here, a 45-kDa isoform of PLZF without a BTB domain was identified via yeast two-hybrid screening using the C-terminal region of ATP7B as bait in our determination of the biological roles of the Wilson disease protein outside of its copper-binding domain. Our immunoprecipitation experiments showed that the hepatocytic isoform of PLZF could specifically interact with the C-terminal region of ATP7B. The immunostaining of HepG2 cells revealed that the ATP7B and PLZF proteins were apparently colocalized into the trans-Golgi complexes. It was also determined that disruption of PLZF expression in the HepG2 cells affected an attenuation of ERK activity in a dose-dependent manner. The hepatocytic activities of ERK kinase were found to be enhanced as the result of PLZF or ATP7B expression, but this enhancement was abrogated by the deletion of the C-terminal region of ATP7B. Furthermore, a transgenic Drosophila strain that ectopically expressed the hepatocytic deltaBTB-PLZF exhibited phenotypic changes in eye and wing development, and these alterations were fully recovered as the result of ATP7B expression, indicating the obvious in vivo interaction between the two proteins. Those PLZF-induced abnormalities were attributed to the enhancement of ERK signaling, as was shown by phenotypic reversions with loss-of-function mutations in ERK signal transduction in Drosophila. These data suggest the existence of a mechanism that regulates ERK signaling via the C-terminus of ATP7B and the ATP7B-interacting hepatocytic PLZF.
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  18. (2005) Guidez F, Howell L, Isalan M, Cebrat M, Alani RM, Ivins S, Hormaeche I, McConnell MJ, Pierce S, Cole PA, Licht J, Zelent A. Histone acetyltransferase activity of p300 is required for transcriptional repression by the promyelocytic leukemia zinc finger protein. Mol. Cell. Biol., 25(13):5552-66.
    Histone acetyltransferase (HAT) activities of proteins such as p300, CBP, and P/CAF play important roles in activation of gene expression. We now show that the HAT activity of p300 can also be required for down-regulation of transcription by a DNA binding repressor protein. Promyelocytic leukemia zinc finger (PLZF), originally identified as a fusion with retinoic acid receptor alpha in rare cases of all-trans-retinoic acid-resistant acute promyelocytic leukemia, is a transcriptional repressor that recruits histone deacetylase-containing corepressor complexes to specific DNA binding sites. PLZF associates with p300 in vivo, and its ability to repress transcription is specifically dependent on HAT activity of p300 and acetylation of lysines in its C-terminal C2-H2 zinc finger motif. An acetylation site mutant of PLZF does not repress transcription and is functionally deficient in a colony suppression assay despite retaining its abilities to interact with corepressor/histone deacetylase complexes. This is due to the fact that acetylation of PLZF activates its ability to bind specific DNA sequences both in vitro and in vivo. Taken together, our results indicate that a histone deacetylase-dependent transcriptional repressor can be positively regulated through acetylation and point to an unexpected role of a coactivator protein in transcriptional repression.
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  19. (2003) Ivins S, Pemberton K, Guidez F, Howell L, Krumlauf R, Zelent A. Regulation of Hoxb2 by APL-associated PLZF protein. Oncogene, 22(24):3685-97.
    The PLZF gene is translocated in a subset of all-trans-retinoic acid resistant acute promyelocytic leukaemia (APL) cases, encodes a DNA binding transcription factor and is expressed highly in haematopoietic progenitor cells as well-developing central nervous system (CNS). The spatially restricted and temporally dynamic pattern of PLZF expression in the developing CNS suggested that it might play a role in the circuitry regulating hindbrain segmentation. We have now identified a PLZF binding site (PLZF-RE) in an enhancer region of Hoxb2 that itself is required for directing high-level expression in rhombomers 3 and 5 of the developing hindbrain. The wild-type r3/r5 enhancer linked to a heterologous promoter was responsive to regulation by PLZF, and this activity was lost in variants containing a mutated PLZF-RE. Compared with the wild-type protein, the binding of the APL-associated reciprocal RARalpha-PLZF fusion to PLZF-RE was much stronger, suggesting that the N-terminal PLZF sequences missing from the fusion may play a role in the regulation of DNA binding. Consistent with this, the N-terminal POZ domain was required for cooperative binding of PLZF to a multimerized PLZF-RE. In the context of the r3/r5 enhancer, the PLZF-RE cooperated for PLZF binding with an additional A/T-rich motif positioned downstream of the PLZF-RE. This A/T motif was previously shown to be essential for the regulation of Hoxb2 expression in r3 and r5 in cooperation with another Krüppel-like zinc finger protein Krox 20. The presence of both the PLZF-RE and the A/T-rich motif was required for a maximal effect of PLZF on a heterologous promoter and was essential in vivo to direct the expression of a lacZ reporter in the chick neural tube. Hence, both PLZF and Krox20 cooperate with a common A/T motif in mediating in vivo activity of the Hoxb2 enhancer. Our findings indicate that Hoxb2 is a direct target for regulation by PLZF in the developing CNS and suggest that deregulation of Hox gene expression may contribute to APL pathogenesis.
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  20. (2003) McConnell MJ, Chevallier N, Berkofsky-Fessler W, Giltnane JM, Malani RB, Staudt LM, Licht JD. Growth suppression by acute promyelocytic leukemia-associated protein PLZF is mediated by repression of c-myc expression. Mol. Cell. Biol., 23(24):9375-88.
    The transcriptional repressor PLZF was identified by its translocation with retinoic acid receptor alpha in t(11;17) acute promyelocytic leukemia (APL). Ectopic expression of PLZF leads to cell cycle arrest and growth suppression, while disruption of normal PLZF function is implicated in the development of APL. To clarify the function of PLZF in cell growth and survival, we used an inducible PLZF cell line in a microarray analysis to identify the target genes repressed by PLZF. One prominent gene identified was c-myc. The array analysis demonstrated that repression of c-myc by PLZF led to a reduction in c-myc-activated transcripts and an increase in c-myc-repressed transcripts. Regulation of c-myc by PLZF was shown to be both direct and reversible. An interaction between PLZF and the c-myc promoter could be detected both in vitro and in vivo. PLZF repressed the wild-type c-myc promoter in a reporter assay, dependent on the integrity of the binding site identified in vitro. PLZF binding in vivo was coincident with a decrease in RNA polymerase occupation of the c-myc promoter, indicating that repression occurred via a reduction in the initiation of transcription. Finally, expression of c-myc reversed the cell cycle arrest induced by PLZF. These data suggest that PLZF expression maintains a cell in a quiescent state by repressing c-myc expression and preventing cell cycle progression. Loss of this repression through the translocation that occurs in t(11;17) would have serious consequences for cell growth control.
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  21. (2002) Melnick A, Carlile G, Ahmad KF, Kiang CL, Corcoran C, Bardwell V, Prive GG, Licht JD. Critical residues within the BTB domain of PLZF and Bcl-6 modulate interaction with corepressors. Mol. Cell. Biol., 22(6):1804-18.
    The PLZF (promyelocytic leukemia zinc finger) transcriptional repressor, when fused to retinoic acid receptor alpha (RARalpha), causes a refractory form of acute promyelocytic leukemia. The highly conserved N-terminal BTB (bric a brac, tramtrack, broad complex)/POZ domain of PLZF plays a critical role in this disease, since it is required for transcriptional repression by the PLZF-RARalpha fusion protein. The crystal structure of the PLZF BTB domain revealed an obligate homodimer with a highly conserved charged pocket formed by apposition of the two monomers. An extensive structure-function analysis showed that the charged pocket motif plays a major role in transcriptional repression by PLZF. We found that mutations of the BTB domain that neutralize key charged pocket residues did not disrupt dimerization, yet abrogated the ability of PLZF to repress transcription and led to the loss of interaction with N-CoR, SMRT, and histone deacetylases (HDACs). We extended these studies to the Bcl-6 protein, which is linked to the pathogenesis of non-Hodgkin's lymphomas. In this case, neutralizing the charged pocket also resulted in loss of repression and corepressor binding. Experiments with purified protein showed that corepressor-BTB interactions were direct. A comparison of the PLZF, Bcl-6, and the FAZF (Fanconi anemia zinc finger)/ROG protein shows that variations in the BTB pocket result in differential affinity for corepressors, which predicts the potency of transcriptional repression. Thus, the BTB pocket represents a molecular structure involved in recruitment of transcriptional repression complexes to target promoters.
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  22. (1999) Zhang T, Xiong H, Kan LX, Zhang CK, Jiao XF, Fu G, Zhang QH, Lu L, Tong JH, Gu BW, Yu M, Liu JX, Licht J, Waxman S, Zelent A, Chen E, Chen SJ. Genomic sequence, structural organization, molecular evolution, and aberrant rearrangement of promyelocytic leukemia zinc finger gene. Proc. Natl. Acad. Sci. U.S.A., 96(20):11422-7.
    The promyelocytic leukemia zinc finger gene (PLZF) is involved in chromosomal translocation t(11;17) associated with acute promyelocytic leukemia. In this work, a 201-kilobase genomic DNA region containing the entire PLZF gene was sequenced. Repeated elements account for 19.83%, and no obvious coding information other than PLZF is present over this region. PLZF contains six exons and five introns, and the exon organization corresponds well with protein domains. There are at least four alternative splicings (AS-I, -II, -III, and -IV) within exon 1. AS-I could be detected in most tissues tested whereas AS-II, -III, and -IV were present in the stomach, testis, and heart, respectively. Although splicing donor and acceptor signals at exon-intron boundaries for AS-I and exons 1-6 were classical (gt-ag), AS-II, -III, and -IV had atypical splicing sites. These alternative splicings, nevertheless, maintained the ORF and may encode isoforms with absence of important functional domains. In mRNA species without AS-I, there is a relatively long 5' UTR of 6.0 kilobases. A TATA box and several transcription factor binding sites were found in the putative promoter region upstream of the transcription start site. PLZF is a well conserved gene from Caenorhabditis elegans to human. PLZF paralogous sequences are found in human genome. The presence of two MLL/PLZF-like alignments on human chromosome 11q23 and 19 suggests a syntenic replication during evolution. The chromosomal breakpoints and joining sites in the index acute promyelocytic leukemia case with t(11;17) also were characterized, which suggests the involvement of DNA damage-repair mechanism.
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  23. (1999) Yeyati PL, Shaknovich R, Boterashvili S, Li J, Ball HJ, Waxman S, Nason-Burchenal K, Dmitrovsky E, Zelent A, Licht JD. Leukemia translocation protein PLZF inhibits cell growth and expression of cyclin A. Oncogene, 18(4):925-34.
    The PLZF gene was identified by its fusion with the RARalpha locus in a therapy resistant form of acute promyelocytic leukemia (APL) associated with the t(11;17)(q23;q21) translocation. Here we describe PLZF as a negative regulator of cell cycle progression ultimately leading to growth suppression. PLZF can bind and repress the cyclin A2 promoter while expression of cyclin A2 reverts the growth suppressed phenotype of myeloid cells expressing PLZF. In contrast RARalpha-PLZF, a fusion protein generated in t(11;17)(q23;q21)-APL activates cyclin A2 transcription and allows expression of cyclin A in anchorage-deprived NIH3T3 cells. Therefore, cyclin A2 is a candidate target gene for PLZF and inhibition of cyclin A expression may contribute to the growth suppressive properties of PLZF. Deregulation of cyclin A2 by RARalpha-PLZF may represent an oncogenic mechanism of this chimeric protein and contribute to the aggressive clinical phenotype of t(11;17)(q23;q21)-associated APL.
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  24. (1999) Ball HJ, Melnick A, Shaknovich R, Kohanski RA, Licht JD. The promyelocytic leukemia zinc finger (PLZF) protein binds DNA in a high molecular weight complex associated with cdc2 kinase. Nucleic Acids Res., 27(20):4106-13.
    A binding site selection from a CpG island library for the promyelocytic leukemia zinc finger protein (PLZF) identified two high affinity PLZF binding sites. These sequences also bound RARalpha/PLZF, a fusion protein formed in chromosomal translocation t(11;17)(q23;q21) associated with acute promyelocytic leukemia. PLZF bound DNA as a slowly migrating complex with an estimated mol. wt of 600 kDa whose formation was dependent on the POZ/dimerization domain of PLZF. The PLZF-DNA complex was unable to form in the presence of cdc2 antibodies. A PLZF-cdc2 interaction was further demonstrated by co-immunoprecipitation and a biotin-streptavidin pull-down assay. PLZF is a phosphoprotein and immunoprecipi-tates with a cdc2-like kinase activity. The PLZF-DNA complex was abolished with the addition of a phosphatase. These studies suggest that the activity of PLZF, a regulator of the cell cycle, may be modulated by cell cycle proteins. RARalpha/PLZF did not complex with cdc2, this potentially contributing to its aberrant transcriptional properties and potential role in leukemo-genesis.
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