Molecular and Cellular Biology (MOL CELL BIOL)

Publications in this journal

• Article: Fendiline inhibits K-Ras plasma membrane localization and blocks K-Ras signal transmission

  Dharini Van Der Hoeven, Kwang-Jin Cho, Xiaoping Ma, Sravanthi Chigurupati, Robert G. Parton, John F. Hancock
  Molecular and Cellular Biology 11/2012;
• Article: The forkhead transcription factor FOXM1 controls cell cycle-dependent gene expression through an atypical chromatin binding mechanism.

  Xi Chen, Gerd A. Müller, Marianne Quaas, Martin Fischer, Namshik Han, Benjamin Stutchbury, Andrew D. Sharrocks, Kurt Engeland
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  ABSTRACT: There are nearly fifty Forkhead (FOX) transcription factors encoded in the human genome and due to sharing a common DNA binding domain, they are all thought to bind to similar DNA sequences. It is therefore unclear how these transcription factors are targeted to specific chromatin regions to elicit specific biological effects. Here we used ChIP-seq to investigate the genome-wide chromatin binding mechanisms used by the forkhead transcription factor FOXM1. In keeping with its previous association with cell cycle control, we demonstrate that FOXM1 binds and regulates a group of genes which are mainly involved in controlling late cell cycle events in the G2 and M phases. However, rather than being recruited through canonical RYAAAYA forkhead binding motifs, FOXM1 binding is directed via CHR elements. FOXM1 binds these elements through protein-protein interactions with the MMB transcriptional activator complex. Thus, we have uncovered a novel and unexpected mode of chromatin binding of a FOX transcription factor which allows it to specifically control cell cycle-dependent gene expression.
  Molecular and Cellular Biology 10/2012;
• Article: β1 integrin NPXY motifs regulate kidney collecting-duct development and maintenance by induced-fit interactions with cytosolic proteins

  Mathew S, Lu Z, Palamuttam RJ, Mernaugh G, Hadziselimovic A, Chen J, Bulus N, Gewin LS, Voehler M, Meves A, Ballestrem C, Fässler R, Pozzi A, Sanders CR, Zent R
  Molecular and Cellular Biology 08/2012; 32(20):4081-4091.
• Article: Prostate apoptosis response 4 (Par-4), a novel substrate of caspase-3 during apoptosis activation.

  Chaudhry P, Singh M, Parent S, Asselin E
  Molecular and Cellular Biology 02/2012;
• Article: The E3 ubiquitin ligase TRAF6 intercedes starvation-induced skeletal muscle atrophy through multiple mechanisms.

  Paul PK, Bhatnagar S, Mishra V, Srivastava S, Darnay BG, Choi Y, Kumar A
  Molecular and Cellular Biology 01/2012;
• Article: Identification of a Src Tyrosine Kinase/SIAH2 E3 Ubiquitin Ligase Pathway that Regulates C/EBPδ Expression and Contributes to Transformation of Breast Tumor Cells.

  RoySarka T, Sharan S, Wang J, Pawar SA, Cantwell CA, Johnson PF, Morrison DK, Wang JM, Sterneck E
  Molecular and Cellular Biology 01/2012; 32(2):320-332.
• Article: PERK is required in the adult pancreas and is essential for maintenance of glucose homeostasis.

  Gao Y, Sartori DJ, Li C, Yu QC, Kushner JA, Simon MC, Diehl JA
  Molecular and Cellular Biology 01/2012; 32(24):5129-39.
• Article: Therapeutic levels of the HMG-CoA reductase inhibitor lovastatin activate Ras signaling via phospholipase D2

  • Kwang-jin Cho, Michelle M Hill, Sravanthi Chigurupati, Guangwei Du, Robert G Parton, John F Hancock
  Molecular and Cellular Biology 03/2011;
• Article: PTEN represses RNA polymerase III-dependent transcription by targeting the TFIIIB complex.

  Annette Woiwode, Sandra A S Johnson, Shuping Zhong, Cheng Zhang, Robert G Roeder, Martin Teichmann, Deborah L Johnson
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  ABSTRACT: PTEN, a tumor suppressor whose function is frequently lost in human cancers, possesses a lipid phosphatase activity that represses phosphatidylinositol 3-kinase (PI3K) signaling, controlling cell growth, proliferation, and survival. The potential for PTEN to regulate the synthesis of RNA polymerase (Pol) III transcription products, including tRNAs and 5S rRNAs, was evaluated. The expression of PTEN in PTEN-deficient cells repressed RNA Pol III transcription, whereas decreased PTEN expression enhanced transcription. Transcription repression by PTEN was uncoupled from PTEN-mediated effects on the cell cycle and was independent of p53. PTEN acts through its lipid phosphatase activity, inhibiting the PI3K/Akt/mTOR/S6K pathway to decrease transcription. PTEN, through the inactivation of mTOR, targets the TFIIIB complex, disrupting the association between TATA-binding protein and Brf1. Kinetic analysis revealed that PTEN initially induces a decrease in the serine phosphorylation of Brf1, leading to a selective reduction in the occupancy of all TFIIIB subunits on tRNA(Leu) genes, whereas prolonged PTEN expression results in the enhanced serine phosphorylation of Bdp1. Together, these results demonstrate a new class of genes regulated by PTEN through its ability to repress the activation of PI3K/Akt/mTOR/S6K signaling.
  Molecular and Cellular Biology 06/2008; 28(12):4204-14.
• Article: PTEN Represses RNA Polymerase III-Dependent Transcription by Targeting the TFIIIB Complex

  Annette Woiwode, Sandra A. S. Johnson, Shuping Zhong, Cheng Zhang, Robert G. Roeder, Martin Teichmann, Deborah L. Johnson
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  ABSTRACT: PTEN, a tumor suppressor whose function is frequently lost in human cancers, possesses a lipid phosphatase activity that represses phosphatidylinositol 3-kinase (PI3K) signaling, controlling cell growth, proliferation, and survival. The potential for PTEN to regulate the synthesis of RNA polymerase (Pol) III transcription products, including tRNAs and 5S rRNAs, was evaluated. The expression of PTEN in PTEN-deficient cells repressed RNA Pol III transcription, whereas decreased PTEN expression enhanced transcription. Transcription repression by PTEN was uncoupled from PTEN-mediated effects on the cell cycle and was independent of p53. PTEN acts through its lipid phosphatase activity, inhibiting the PI3K/Akt/mTOR/S6K pathway to decrease transcription. PTEN, through the inactivation of mTOR, targets the TFIIIB complex, disrupting the association between TATA-binding protein and Brf1. Kinetic analysis revealed that PTEN initially induces a decrease in the serine phosphorylation of Brf1, leading to a selective reduction in the occupancy of all TFIIIB subunits on tRNALeu genes, whereas prolonged PTEN expression results in the enhanced serine phosphorylation of Bdp1. Together, these results demonstrate a new class of genes regulated by PTEN through its ability to repress the activation of PI3K/Akt/mTOR/S6K signaling.
  Molecular and Cellular Biology 06/2008; 28(12):4204.
• Article: HIV-1 Vpr-binding protein VprBP, a WD40 protein associated with the DDB1-CUL4 E3 ubiquitin ligase, is essential for DNA replication and embryonic development

  McCall, C.M, Miliani de Marval, P.L, Chastain, P.D. II, Jackson, S.C, He, Y.J, Kotake, Cook, J.G, Xiong
  Molecular and Cellular Biology 01/2008;
• Article: An intronic locus control region plays an essential role in the establishment of an autonomous hepatic chromatin domain for the human vitamin D-binding protein gene.

  Tomoko Hiroki, Stephen A Liebhaber, Nancy E Cooke
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  ABSTRACT: The human vitamin D-binding protein (hDBP) gene exists in a cluster of four liver-expressed genes. A minimal hDBP transgene, containing a defined set of liver-specific DNase I hypersensitive sites (HSs), is robustly expressed in mouse liver in a copy-number-dependent manner. Here we evaluate these HSs for function. Deletion of HSI, located 5' to the promoter (kb -2.1) had no significant effect on hDBP expression. In contrast, deletion of HSIV and HSV from intron 1 repressed hDBP expression and eliminated copy number dependency without a loss of liver specificity. Chromatin immunoprecipitation analysis revealed peaks of histone H3 and H4 acetylation coincident with HSIV in the intact hDBP locus. This region contains a conserved array of binding sites for the liver-enriched transcription factor C/EBP. In vitro studies revealed selective binding of C/EBPalpha to HSIV. In vivo occupancy of C/EBPalpha at HSIV was demonstrated in hepatic chromatin, and depletion of C/EBPalpha in a hepatic cell line decreased hDBP expression. A nonredundant role for C/EBPalpha was confirmed in vivo by demonstrating a reduction of hDBP expression in C/EBPalpha-null mice. Parallel studies revealed in vivo occupancy of the liver-enriched factor HNF1alpha at HSIII (at kb 0.13) within the hDBP promoter. These data demonstrate a critical role for elements within intron 1 in the establishment of an autonomous and productive hDBP chromatin locus and suggest that this function is dependent upon C/EBPalpha. Cooperative interactions between these intronic complexes and liver-restricted complexes within the target promoter are likely to underlie the consistency and liver specificity of the hDBP activation.
  Molecular and Cellular Biology 12/2007; 27(21):7365-80.
• Article: Requirement of RAD52 group genes for postreplication repair of UV-damaged DNA in Saccharomyces cerevisiae.

  Venkateswarlu Gangavarapu, Satya Prakash, Louise Prakash
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  ABSTRACT: In Saccharomyces cerevisiae, replication through DNA lesions is promoted by Rad6-Rad18-dependent processes that include translesion synthesis by DNA polymerases eta and zeta and a Rad5-Mms2-Ubc13-controlled postreplicational repair (PRR) pathway which repairs the discontinuities in the newly synthesized DNA that form opposite from DNA lesions on the template strand. Here, we examine the contributions of the RAD51, RAD52, and RAD54 genes and of the RAD50 and XRS2 genes to the PRR of UV-damaged DNA. We find that deletions of the RAD51, RAD52, and RAD54 genes impair the efficiency of PRR and that almost all of the PRR is inhibited in the absence of both Rad5 and Rad52. We suggest a role for the Rad5 pathway when the lesion is located on the leading strand template and for the Rad52 pathway when the lesion is located on the lagging strand template. We surmise that both of these pathways operate in a nonrecombinational manner, Rad5 by mediating replication fork regression and template switching via its DNA helicase activity and Rad52 via a synthesis-dependent strand annealing mode. In addition, our results suggest a role for the Rad50 and Xrs2 proteins and thereby for the MRX complex in promoting PRR via both the Rad5 and Rad52 pathways.
  Molecular and Cellular Biology 12/2007; 27(21):7758-64.
• Article: Nemo-like kinase-myocyte enhancer factor 2A signaling regulates anterior formation in Xenopus development.

  Kiyotoshi Satoh, Junji Ohnishi, Atsushi Sato, Michio Takeyama, Shun-ichiro Iemura, Tohru Natsume, Hiroshi Shibuya
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  ABSTRACT: The development of anterior neural structure in Xenopus laevis requires the inhibition of bone morphogenic protein 4 and Wnt signaling. We previously reported that Nemo-like kinase (NLK) negatively regulates Wnt signaling via the phosphorylation of T-cell factor/lymphoid enhancer factor. However, the molecular events occurring downstream of NLK pathways in early neural development remain unclear. In the present study, we identified the transcription factor myocyte enhancer factor 2A (MEF2A) as a novel substrate for NLK. NLK regulates the function of Xenopus MEF2A (xMEF2A) via phosphorylation, and this modification can be inhibited by the depletion of endogenous NLK. In Xenopus embryos, the depletion of either NLK or MEF2A results in a severe defect in anterior development. The endogenous expression of anterior markers was blocked by the depletion of endogenous Xenopus NLK (xNLK) or xMEF2A but, notably, not by the depletion of other xMEF2 family proteins, xMEF2C and xMEF2D. Defects in head formation or the expression of the anterior marker genes caused by the depletion of endogenous xMEF2A could be eliminated by the expression of wild-type xMEF2A, but not xMEF2A containing mutated xNLK phosphorylation sites. Furthermore, the expression of xNLK-induced anterior markers was efficiently blocked by the depletion of endogenous xMEF2A in animal pole explants. These results show that NLK specifically regulates the MEF2A activity required for anterior formation in Xenopus development.
  Molecular and Cellular Biology 12/2007; 27(21):7623-30.
• Article: PITX2 and beta-catenin interactions regulate Lef-1 isoform expression.

  Melanie Amen, Xiaoming Liu, Usha Vadlamudi, Gabriela Elizondo, Evan Diamond, John F Engelhardt, Brad A Amendt
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  ABSTRACT: Lef-1 and PITX2 function in the Wnt signaling pathway by recruiting and interacting with beta-catenin to activate target genes. Chromatin immunoprecipitation (ChIP) assays identified the Lef-1 promoter as a PITX2 downstream target. Transgenic mice expressing LacZ driven by the 2.5-kb LEF-1 promoter demonstrated expression in the tooth epithelium correlated with endogenous Lef-1 FL epithelial expression. PITX2 isoforms regulate the LEF-1 promoter, and beta-catenin synergistically enhanced activation of the LEF-1 promoter in combination with PITX2 and Lef-1 isoforms. PITX2 enhances endogenous expression of the full-length beta-catenin-dependent Lef-1 isoform (Lef-1 FL) while decreasing expression of the N-terminally truncated beta-catenin-independent isoform. Our research revealed a novel interaction between PITX2, Lef-1, and beta-catenin in which the Lef-1 beta-catenin binding domain is dispensable for its interaction with PITX2. PITX2 interacts with two sites within the Lef-1 protein. Furthermore, beta-catenin interacts with the PITX2 homeodomain and Lef-1 interacts with the PITX2 C-terminal tail. Lef-1 and beta-catenin interact simultaneously and independently with PITX2 through two different sites to regulate PITX2 transcriptional activity. These data support a role for PITX2 in cell proliferation, migration, and cell division through differential Lef-1 isoform expression and interactions with Lef-1 and beta-catenin.
  Molecular and Cellular Biology 12/2007; 27(21):7560-73.
• Article: Restricting conformational flexibility of the switch II region creates a dominant-inhibitory phenotype in Obg GTPase Nog1.

  Yevgeniya R Lapik, Julia M Misra, Lester F Lau, Dimitri G Pestov
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  ABSTRACT: Nog1 is a conserved eukaryotic GTPase of the Obg family involved in the biogenesis of 60S ribosomal subunits. Here we report the unique dominant-inhibitory properties of a point mutation in the switch II region of mouse Nog1; this mutation is predicted to restrict conformational mobility of the GTP-binding domain. We show that although the mutation does not significantly affect GTP binding, ectopic expression of the mutant in mouse cells disrupts productive assembly of pre-60S subunits and arrests cell proliferation. The mutant impairs processing of multiple pre-rRNA intermediates, resulting in the degradation of the newly synthesized 5.8S/28S rRNA precursors. Sedimentation analysis of nucleolar preribosomes indicates that defective Nog1 function inhibits the conversion of 32S pre-rRNA-containing complexes to a smaller form, resulting in a drastic accumulation of enlarged pre-60S particles in the nucleolus. These results suggest that conformational changes in the switch II element of Nog1 have a critical importance for the dissociation of preribosome-bound factors during intranucleolar maturation and thereby strongly influence the overall efficiency of the assembly process.
  Molecular and Cellular Biology 12/2007; 27(21):7735-44.
• Article: A regulatory circuit mediating convergence between Nurr1 transcriptional regulation and Wnt signaling.

  Hirochika Kitagawa, William J Ray, Helmut Glantschnig, Pascale V Nantermet, Yuanjiang Yu, Chih-Tai Leu, Shun-ichi Harada, Shigeaki Kato, Leonard P Freedman
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  ABSTRACT: The orphan nuclear receptor Nurr1 is essential for the development and maintenance of midbrain dopaminergic neurons, the cells that degenerate during Parkinson's disease, by promoting the transcription of genes involved in dopaminergic neurotransmission. Since Nurr1 lacks a classical ligand-binding pocket, it is not clear which factors regulate its activity and how these factors are affected during disease pathogenesis. Since Wnt signaling via beta-catenin promotes the differentiation of Nurr1(+) dopaminergic precursors in vitro, we tested for functional interactions between these systems. We found that beta-catenin and Nurr1 functionally interact at multiple levels. In the absence of beta-catenin, Nurr1 is associated with Lef-1 in corepressor complexes. Beta-catenin binds Nurr1 and disrupts these corepressor complexes, leading to coactivator recruitment and induction of Wnt- and Nurr1-responsive genes. We then identified KCNIP4/calsenilin-like protein as being responsive to concurrent activation by Nurr1 and beta-catenin. Since KCNIP4 interacts with presenilins, the Alzheimer's disease-associated proteins that promote beta-catenin degradation, we tested the possibility that KCNIP4 induction regulates beta-catenin signaling. KCNIP4 induction limited beta-catenin activity in a presenilin-dependent manner, thereby serving as a negative feedback loop; furthermore, Nurr1 inhibition of beta-catenin activity was absent in PS1(-/-) cells or in the presence of small interfering RNAs specific to KCNIP4. These data describe regulatory convergence between Nurr1 and beta-catenin, providing a mechanism by which Nurr1 could be regulated by Wnt signaling.
  Molecular and Cellular Biology 12/2007; 27(21):7486-96.
• Article: DLGH1 is a negative regulator of T-lymphocyte proliferation.

  Linda M Stephenson, Bénédicte Sammut, Daniel B Graham, Joaquim Chan-Wang, Karry L Brim, Alan S Huett, Ana V Miletic, Tracie Kloeppel, Aimee Landry, Ramnik Xavier, Wojciech Swat
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  ABSTRACT: Discs large homolog 1 (DLGH1), a founding member of the membrane-associated guanylate kinase family of proteins containing PostSynaptic Density-95/Discs large/Zona Occludens-1 domains, is an ortholog of the Drosophila tumor suppressor gene Discs large. In the mammalian embryo, DLGH1 is essential for normal urogenital morphogenesis and the development of skeletal and epithelial structures. Recent reports also indicate that DLGH1 may be a critical mediator of signals triggered by the antigen receptor complex in T lymphocytes by functioning as a scaffold coordinating the activities of T-cell receptor (TCR) signaling proteins at the immune synapse. However, it remains unclear if DLGH1 functions to enhance or attenuate signals emanating from the TCR. Here, we used Dlgh1 gene-targeted mice to determine the requirement for DLGH1 in T-cell development and activation. Strikingly, while all major subsets of T cells appear to undergo normal thymic development in the absence of DLGH1, peripheral lymph node Dlgh1(-/-) T cells show a hyper-proliferative response to TCR-induced stimulation. These data indicate that, consistent with the known function of Discs large proteins as tumor suppressors and attenuators of cell division, in T lymphocytes, DLGH1 functions as a negative regulator of TCR-induced proliferative responses.
  Molecular and Cellular Biology 12/2007; 27(21):7574-81.