Maria Isabel Tussie-Luna

Tufts University, Georgia, United States

Are you Maria Isabel Tussie-Luna?

Claim your profile

Publications (12)83.2 Total impact

  • Maria B Lazebnik, Maria Isabel Tussie-Luna, Philip W Hinds, Ananda L Roy
    [Show abstract] [Hide abstract]
    ABSTRACT: Williams-Beuren syndrome (WBS), an autosomal dominant genetic disorder, is characterized by a unique cognitive profile and craniofacial defects. WBS results from a microdeletion at the chromosomal location 7q11.23 that encompasses the genes encoding the members of TFII-I family of transcription factors. Given that the haploinsufficiency for TFII-I is causative to the craniofacial phenotype in humans, we set out to analyze the effect of post-transcriptional silencing of TFII-I during BMP-2-driven osteoblast differentiation in the C2C12 cell line. Our results show that TFII-I plays an inhibitory role in regulating genes that are essential in osteogenesis and intersects with the bone-specific transcription factor Runx2 and the retinoblastoma protein, pRb. Identification of pathways regulated by TFII-I family transcription factors may begin to shed light on the molecular determinants of WBS.
    Journal of Biological Chemistry 10/2009; 284(52):36234-9. · 4.65 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: GTF2I and GTF2IRD1 encoding the multifunctional transcription factors TFII-I and BEN are clustered at the 7q11.23 region hemizygously deleted in Williams-Beuren syndrome (WBS), a complex multisystemic neurodevelopmental disorder. Although the biochemical properties of TFII-I family transcription factors have been studied in depth, little is known about the specialized contributions of these factors in pathways required for proper embryonic development. Here, we show that homozygous loss of either Gtf2ird1 or Gtf2i function results in multiple phenotypic manifestations, including embryonic lethality; brain hemorrhage; and vasculogenic, craniofacial, and neural tube defects in mice. Further analyses suggest that embryonic lethality may be attributable to defects in yolk sac vasculogenesis and angiogenesis. Microarray data indicate that the Gtf2ird1 homozygous phenotype is mainly caused by an impairment of the genes involved in the TGFbetaRII/Alk1/Smad5 signal transduction pathway. The effect of Gtf2i inactivation on this pathway is less prominent, but downregulation of the endothelial growth factor receptor-2 gene, resulting in the deterioration of vascular signaling, most likely exacerbates the severity of the Gtf2i mutant phenotype. A subset of Gtf2ird1 and Gtf2i heterozygotes displayed microcephaly, retarded growth, and skeletal and craniofacial defects, therefore showing that haploinsufficiency of TFII-I proteins causes various developmental anomalies that are often associated with WBS.
    Proceedings of the National Academy of Sciences 01/2009; 106(1):181-6. · 9.81 Impact Factor
  • Maria B Lazebnik, Maria Isabel Tussie-Luna, Ananda L Roy
    [Show abstract] [Hide abstract]
    ABSTRACT: The ubiquitously expressed TFII-I family of multifunctional transcription factors is involved in gene regulation as well as signaling. Despite the fact that they share significant sequence homology, these factors exhibit varied and distinct functions. The lack of knowledge about its binding sites and physiological target genes makes it more difficult to assign a definitive function for the TFII-I-related protein, BEN. We set out to determine its optimal binding site with the notion of predicting its physiological target genes. Here we report the identification of an optimal binding sequence for BEN by SELEX (systematic evolution of ligands by exponential enrichment) and confirm the relevance of this sequence by functional assays. We further performed a data base search to assign genes that have this consensus site(s) and validate several candidate genes by quantitative PCR upon stable silencing of BEN and by chromatin immunoprecipitation assay upon stable expression of BEN. Given that haploinsufficiency in BEN is causative to Williams-Beuren syndrome, these results may further lead to the identification of a set of physiologically relevant target genes for BEN and may help identify molecular determinants of Williams-Beuren syndrome.
    Journal of Biological Chemistry 05/2008; 283(17):11078-82. · 4.65 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Multifunctional transcription factor TFII-I has two spliced isoforms (Delta and beta) in murine fibroblasts. Here we show that these isoforms have distinct subcellular localization and mutually exclusive transcription functions in the context of growth factor signaling. In the absence of signaling, TFII-Ibeta is nuclear and recruited to the c-fos promoter in vivo. But upon growth factor stimulation, the promoter recruitment is abolished and it is exported out of the nucleus. Moreover, isoform-specific silencing of TFII-Ibeta results in transcriptional activation of the c-fos gene. In contrast, TFII-IDelta is largely cytoplasmic in the resting state but translocates to the nucleus upon growth factor signaling, undergoes signal-induced recruitment to the same site on the c-fos promoter, and activates the gene. Importantly, activated TFII-IDelta interacts with Erk1/2 (MAPK) kinase in the cell cytoplasm and imports the Erk1/2 to the nucleus, thereby transducing growth factor signaling. Our results identify a unique growth factor signaling pathway controlled by opposing activities of two TFII-I spliced isoforms.
    Molecular Cell 11/2006; 24(2):301-8. · 15.28 Impact Factor
  • Source
    M I Tussié-Luna, L Rozo, A L Roy
    [Show abstract] [Hide abstract]
    ABSTRACT: The promyelocytic leukemia (PML) gene codes for a tumor suppressor protein that is associated with distinct subnuclear macromolecular structures called the PML bodies. The PML gene is frequently involved in the t(15;17) chromosomal translocation of acute promyelocytic leukemia (APL). The translocation results in a fusion gene product, PML-RARalpha, in which the PML gene fuses to the retinoic acid receptor alpha (RARalpha) gene. PML-RARalpha has been shown to promote transcriptional repression of genes involved in myeloid terminal differentiation and to disrupt the architecture of PML bodies, a phenotype reversed by treatment with all trans retinoic acid (ATRA). However, there are several alternatively spliced isoforms of PML-RARalpha. Here, we addressed the differences between the short and the long isoforms of PML-RARalpha (L and S) since both are associated with APL. We demonstrate that PML-RARalphaL, but not PML-RARalphaS, can directly promote cell growth by transcriptionally activating the pro-proliferative gene, c-fos, in response to mitogenic stimulation. The activity of the PML-RARalphaL is completely sensitive to ATRA. We further show that this activation is not via direct recruitment of the protein to the c-fos promoter but indirectly by altering the chromosomal environment of the c-fos gene, thereby rendering it more accessible to the signal induced transcriptional activators. Our results suggest that in addition to antagonizing the PML-tumor suppressor or the PML-pro-apoptotic activity, PML-RARalpha proteins can also directly promote cell growth by activating c-fos.
    Oncogene 07/2006; 25(24):3375-86. · 8.56 Impact Factor
  • Source
    Manching Ku, Sergei Y Sokol, Jack Wu, Maria Isabel Tussie-Luna, Ananda L Roy, Akiko Hata
    [Show abstract] [Hide abstract]
    ABSTRACT: Goosecoid (Gsc) is a homeodomain-containing transcription factor present in a wide variety of vertebrate species and known to regulate formation and patterning of embryos. Here we show that in embryonic carcinoma P19 cells, the transcription factor TFII-I forms a complex with Smad2 upon transforming growth factor beta (TGFbeta)/activin stimulation, is recruited to the distal element (DE) of the Gsc promoter, and activates Gsc transcription. Downregulation of endogenous TFII-I by small inhibitory RNA in P19 cells abolishes the TGFbeta-mediated induction of Gsc. Similarly, Xenopus embryos with endogenous TFII-I expression downregulated by injection of TFII-I-specific antisense oligonucleotides exhibit decreased Gsc expression. Unlike TFII-I, the related factor BEN (binding factor for early enhancer) is constitutively recruited to the distal element in the absence of TGFbeta/activin signaling and is replaced by the TFII-I/Smad2 complex upon TGFbeta/activin stimulation. Overexpression of BEN in P19 cells represses the TGFbeta-mediated transcriptional activation of Gsc. These results suggest a model in which TFII-I family proteins have opposing effects in the regulation of the Gsc gene in response to a TGFbeta/activin signal.
    Molecular and Cellular Biology 09/2005; 25(16):7144-57. · 5.04 Impact Factor
  • Dean Tantin, Maria Isabel Tussie-Luna, Ananda L Roy, Phillip A Sharp
    [Show abstract] [Hide abstract]
    ABSTRACT: The restriction of immunoglobulin variable region promoter activity to B lymphocytes is a well known paradigm of promoter specificity. Recently, a cis-element, located downstream of the transcription initiation site of murine heavy chain variable promoters, was shown to be critical for B cell activity and specificity. Here we show that mutation of this element, termed DICE (Downstream Immunoglobulin Control Element), reduces in vivo activity in B cells. Gel mobility shift assays show that DICE forms B cell-specific complexes that were also sensitive to DICE mutation. DICE mutation strongly reduces the ability of a distal immunoglobulin heavy chain intronic enhancer to stimulate transcription. We also identify a DICE-interacting factor: a TFII-I-related protein known as BEN (also termed Mus-TRD1 and WBSCR11). Dominant-negative and RNAi-mediated knockdown experiments indicate that BEN can both positively and negatively regulate IgH promoter activity, depending on the cell line.
    Journal of Biological Chemistry 03/2004; 279(7):5460-9. · 4.65 Impact Factor
  • Source
    Catarina Sacristán, María Isabel Tussié-Luna, Sheila M Logan, Ananda L Roy
    [Show abstract] [Hide abstract]
    ABSTRACT: TFII-I is a ubiquitously expressed multifunctional transcription factor with broad biological roles in transcription and signal transduction in a variety of cell types. We and others have shown that TFII-I can interact physically and functionally with Bruton's tyrosine kinase (Btk), a hematopoietic non-receptor protein tyrosine kinase that is critical for B lymphocyte development. Although TFII-I-Btk interactions are impaired in B cells from X-linked immunodeficient mice, the precise molecular determinants governing TFII-I-Btk complex formation remain unknown. To this end, we have conducted a structural analysis of TFII-I-Btk interactions by using a panel of TFII-I mutants. These studies have revealed that a region within the N-terminal 90 amino acids of TFII-I, which includes a putative leucine zipper motif, is primarily responsible for its interaction with Btk. Mutations in the leucine zipper region itself were not sufficient to abrogate binding of TFII-I to Btk, suggesting that regions/residues outside the leucine zipper are responsible for such interactions. Because the first 90 amino acids of TFII-I are required for its dimerization, we propose that Btk tethers TFII-I to the cytoplasm by preventing its dimerization and its subsequent nuclear localization. We further examined the requirement of tyrosine phosphorylation for TFII-I-Btk complex formation. Our data showed that Src-dependent tyrosine phosphorylation sites in TFII-I are not targeted by Btk, suggesting that multiple kinases can independently target TFII-I via distinct signaling pathways. Our results provide a beginning step toward understanding the functional importance of the TFII-I-Btk pathway in B cell signaling and gene expression.
    Journal of Biological Chemistry 03/2004; 279(8):7147-58. · 4.65 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: BEN is a member of the TFII-I family of transcription factors, characterized by the presence of multiple helix-loop-helix repeat domains. Our immunohistochemical analysis demonstrated broad and extensive expression of BEN during mouse pre- and postimplantation development, with highest levels occurring during early to midgestation. Maternally expressed BEN is present in both the cytoplasm and nuclei of the zygote; however, it retains a predominantly nuclear localization between the two-cell stage of development and early blastocyst stages. This nuclear expression is observed in most tissues throughout development. Although, it is interesting to note that at E4.5-6.5, during early gastrulation stage, BEN is localized in the cytoplasm. At later stages, BEN retains an extensive expression pattern in a variety of developing systems implicating its involvement in tissue development and organogenesis.
    Gene Expression Patterns 11/2003; 3(5):579-89. · 1.64 Impact Factor
  • Maria Isabel Tussie-Luna, Bertha Michel, Shweta Hakre, Ananda L Roy
    [Show abstract] [Hide abstract]
    ABSTRACT: We have shown previously that a TFII-I-related protein, hMusTRD1/BEN, represses transcriptional activity of TFII-I. The repression by hMusTRD1/BEN was hypothesized to occur via a two-step competition mechanism involving a cytoplasmic shuttling factor and a nuclear cofactor required for transcriptional activation of TFII-I. Employing a two-hybrid approach with both yeast genomic and mouse cDNA libraries in parallel, we have identified the RING-like zinc finger containing Miz1/PIASxbeta/Siz2, which is a ubiquitin-protein isopeptide ligase in the SUMO pathway, as the potential nuclear cofactor that interacts with both TFII-I and hMusTRD1/BEN. Our conclusion is based on the following observations. First, the interactions are biochemically confirmed in mammalian cells where Miz1/mPIASxbeta interacts with both TFII-I and hMusTRD1/BEN when these proteins are ectopically co-expressed. Second, co-expression of a nuclear localization signal-deficient mutant of Miz1/mPIASxbeta with wild type TFII-I fails to alter the subcellular localization of the former. Finally, ectopically expressed Miz1/mPIASxbeta augments the transcriptional activity of TFII-I and relieves the repression exerted by a mutant hMusTRD1/BEN that co-localized with TFII-I in the nucleus.
    Journal of Biological Chemistry 12/2002; 277(45):43185-93. · 4.65 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: TFII-I family proteins are characterized structurally by the presence of multiple reiterated I-repeats, each containing a putative helix-loop-helix domain. Functionally, they behave as multifunctional transcription factors that are activated by a variety of extracellular signals. In studying their subcellular localization, we noticed that these transcription factors frequently reside in subnuclear domains/dots. Because nuclear dots are believed often to harbor components of histone deacetylase enzymes (HDACs), we investigated whether TFII-I family proteins colocalize and interact with HDACs. Here, we show that TFII-I and its related member hMusTRD1/BEN physically and functionally interact with HDAC3. The TFII-I family proteins and HDAC3 also show nearly identical expression patterns in early mouse development. Consistent with our earlier observation that TFII-I family proteins also interact with PIASxbeta, a member of the E3 ligase family involved in the small ubiquitin-like modifier (SUMO) pathway, we show further that PIASxbeta physically and functionally interacts with HDAC3 and relieves the transcriptional repression exerted by HDAC3 upon TFII-I-mediated gene activation. These results suggest a complex interplay between two posttranslational pathways-histone modification and SUMOylation-brokered in part by TFII-I family proteins.
    Proceedings of the National Academy of Sciences 11/2002; 99(20):12807-12. · 9.81 Impact Factor
  • Source
    M I Tussié-Luna, D Bayarsaihan, F H Ruddle, A L Roy
    [Show abstract] [Hide abstract]
    ABSTRACT: TFII-I is an unusual transcription factor possessing both basal and signal-induced transcriptional functions. Here we report the characterization of a TFII-I-related factor (MusTRD1/BEN) that regulates transcriptional functions of TFII-I by controlling its nuclear residency. MusTRD1/BEN has five or six direct repeats, each containing helix--loop--helix motifs, and, thus, belongs to the TFII-I family of transcription factors. TFII-I and MusTRD1/BEN, when expressed individually, show predominant nuclear localization. However, when the two proteins are coexpressed ectopically, MusTRD1/BEN locates almost exclusively to the nucleus, whereas TFII-I is largely excluded from the nucleus, resulting in a loss of TFII-I-dependent transcriptional activation of the c-fos promoter. Mutation of a consensus nuclear localization signal in MusTRD1/BEN results in a reversal of nuclear residency of the two proteins and a concomitant gain of c-fos promoter activity. These data suggest a means of transcriptional repression by competition at the level of nuclear occupancy.
    Proceedings of the National Academy of Sciences 08/2001; 98(14):7789-94. · 9.81 Impact Factor