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PubMed2005

Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors.

Mutations in the MEN1 gene are associated with the multiple endocrine neoplasia syndrome type 1 (MEN1), which is characterized by parathyroid hyperplasia and tumors of the pituitary and pancreatic islets. The mechanism by which MEN1 acts as a tumor suppressor is unclear. We have recently shown that menin, the MEN1 protein product, interacts with mixed lineage leukemia (MLL) family proteins in a histone methyltransferase complex including Ash2, Rbbp5, and WDR5. Here, we show that menin directly regulates expression of the cyclin-dependent kinase inhibitors p27Kip1 and p18Ink4c. Menin activates transcription by means of a mechanism involving recruitment of MLL to the p27Kip1 and p18Ink4c promoters and coding regions. Loss of function of either MLL or menin results in down-regulation of p27Kip1 and p18Ink4c expression and deregulated cell growth. These findings suggest that regulation of cyclin-dependent kinase inhibitor transcription by cooperative interaction between menin and MLL plays a central role in menin's activity as a tumor suppressor.

Carrier Proteins↗
PubMed1984

Molecular cloning and nucleotide sequence of a variant wheat histone H4 gene.

To determine whether there is structural variation among histone H4 genes in wheat, one (TH091) of the H4 genes that had been cloned from a wheat genomic DNA library was sequenced and compared with another H4 gene (TH011) which we had described previously [Tabata et al., Nucl. Acids Res. 11 (1983) 5865-5865]. Nucleotide sequence analysis revealed that there are 17 nucleotide replacements in the protein-coding region of two H4 genes, causing only one amino acid substitution: a glycine at position 4 (from the N terminus) in TH011 was replaced by an aspartic acid in TH091. S1 mapping, using total nuclear RNA from germinated seeds, indicated that the H4 gene was transcribed in vivo.

Amino Acid Sequence↗
PubMed1997

The mouse histone H2a gene contains a small element that facilitates cytoplasmic accumulation of intronless gene transcripts and of unspliced HIV-1-related mRNAs.

Histone mRNAs are naturally intronless and accumulate efficiently in the cytoplasm. To learn whether there are cis-acting sequences within histone genes that allow efficient cytoplasmic accumulation of RNAs, we made recombinant constructs in which sequences from the mouse H2a gene were cloned into a human beta-globin cDNA. By using transient transfection and RNase protection analysis, we demonstrate here that a 100-bp sequence within the H2a coding region permits efficient cytoplasmic accumulation of the globin cDNA transcripts. We also show that this sequence appears to suppress splicing and can functionally replace Rev and the Rev-responsive element in the cytoplasmic accumulation of unspliced HIV-1-related mRNAs. Like the Rev-responsive element, this sequence acts in an orientation-dependent manner. We thus propose that the sequence identified here may be a member of the cis-acting elements that facilitate the cytoplasmic accumulation of naturally intronless gene transcripts.

Animals↗
PubMed1988

Conservation of histone H2A/H2B intergene regions: a role for the H2B specific element in divergent transcription.

The organization and function of potential regulatory elements associated with the promoters of chicken H2A and H2B genes pairs have been examined. The intergene regions of six dispersed and divergently-transcribed H2A/H2B gene pairs contain several extremely well conserved and spaced blocks of sequence homology. Adjacent coding regions are on average 342 base-pairs apart. Respective TATA boxes are separated by 180 base-pairs and within this confined region there are four CCAAT boxes and a previously identified 13 base-pair H2B-specific element (H2B-box) which has homology to the octamer motif present in a number of gene promoter/enhancer elements. Transcription of H2A and H2B genes from wild-type and mutant constructs was measured in transient assays by transfection into HeLa cells, and in permanently transformed clonal cell lines. In vitro separation of the two genes at a unique intergenic site significantly decreased transcription of each gene. This suggested that the H2A/H2B gene pairs contained overlapping promoters. Deletion or point mutagenesis of the H2B-specific element decreased the levels of H2B and the H2A transcripts indicating that this sequence is a common regulatory element of both genes in the divergent-pair configeration.

Animals↗
PubMed1993

Defective Marek's disease virus DNA contains a gene encoding a potential nuclear DNA binding protein and a HSV a-like sequence.

Four RNA transcripts from chicken embryo fibroblast cells infected with Marek's disease virus (MDV) strain 281Ml/1 hybridized to the 4-kbp MDV replicon DNA. In an attempt to identify open reading frames coding for the four transcripts, we determined the nucleotide sequences of 4-kbp replicon DNA (represents a single monomeric repeat unit of defective MDV genome). Computer analysis indicates that the 4-kbp MDV replicon DNA contains two intact open reading frames (ORFs) with common promoter regulatory elements. ORF-A codes for a putative 204 amino acid protein that shares 21 and 36% amino acid sequence identity to nuclear DNA binding proteins such as the EBNA-1 of Epstein-Barr virus and galline, a chicken sperm histone protein, respectively. ORF-B encodes for a potential 350 amino acid protein, which did not show any significant amino acid sequence identity to known protein sequences within Swiss-Protein data base. ORF-B may, therefore, encode a MDV specific protein. The 5'-region of MDV replicon DNA revealed seven reiterated copies of an 11-bp motif sharing 8 out of 11 nucleotide sequence identity to DR2 elements of the herpes simplex virus strain USA-8 a sequence.

Amino Acid Sequence↗
PubMed2026

Decoding context-dependent sirtuin pharmacology in cancer: Metabolic-epigenetic switches and precision therapeutic targeting.

Sirtuins (SIRT1-SIRT7) are a family of NAD+-dependent lysine deacetylases that possess mono-ADP-ribosyltransferase activity and integrate cellular metabolic status with chromatin regulation, genome maintenance, redox homeostasis, immune responses, and adaptation to cancer therapies. Their translational value has been obscured by a recurring paradox: the same isoform may constrain malignant transformation in one setting yet support metastatic competence, stemness, immune evasion, or drug resistance in another. This review reframes that paradox as a measurable problem of context. We define a SIRT context code in which NAD+ availability and compartmentalization, subcellular localization, PTM state, chromatin occupancy, oncogenic genotype, cell lineage, and tumor microenvironment jointly determine sirtuin output. Using recent mechanistic and translational evidence, we summarize how sirtuins regulate metabolic switching, histone acetylation and lactylation, genome stability, cancer-associated fibroblast programs, regulatory T-cell enrichment, cancer stem-cell plasticity, angiogenesis, and resistance to DNA-damaging, targeted, and immune therapies. We further argue that successful sirtuin pharmacology will require context matching rather than indiscriminate activation or inhibition. Priorities include spatial and single-cell biomarker discovery, compartment-specific NAD+ measurements, PTM-resolved activity assays, structure-guided isoform-selective agents, and degrader strategies targeting non-catalytic scaffolding functions. Sirtuins should therefore be viewed as metabolic-epigenetic decision nodes rather than fixed oncogenes or tumor suppressors. However, the evidence remains predominantly preclinical, and our search identified no clinical-stage oncology trials of direct sirtuin modulators using prospective biomarker stratification, underscoring that this framework remains translationally aspirational rather than clinically validated.

Humans↗
PubMed2001

Transcriptional regulation of type III secretion genes in enteropathogenic Escherichia coli: Ler antagonizes H-NS-dependent repression.

Secretion of effector proteins in enteropathogenic Escherichia coli (EPEC) is mediated by a specialized type III secretion system whose components are encoded in the LEE1, LEE2 and LEE3 operons. Using cat transcriptional fusions and primer extension analysis, we determined that the LEE2 and LEE3 operons are expressed from two overlapping divergent promoters, whose expression is negatively regulated by flanking common upstream and downstream silencing regulatory sequences (SRS1 and SRS2). In the absence of either SRS1 or SRS2, expression of the LEE2 and LEE3 operons became independent of Ler, a positive regulatory protein encoded by the first gene of the LEE1 operon. Similarly, in the absence of the histone-like protein H-NS, expression from both promoters became Ler independent even if both SRSs were present. In addition, the efficient expression of both the LEE2 and the LEE3 promoters required PerC (BfpW), a protein coded by the third gene of the per (bfpTVW) locus, but only in the presence of the EAF plasmid. Our deletion analysis also showed that the negative regulation observed in the presence of ammonium or at temperatures above 37 degrees C (e.g. 40 degrees C) required the SRSs or elements located therein. In contrast, the negative regulation observed in LB or at temperatures below 37 degrees C (e.g. 25 degrees C) was still observed even in the absence of both SRSs and seems to act only on the promoters. Together, these results suggest that Ler acts as an antirepressor protein that overcomes the H-NS-mediated silencing on the LEE2/LEE3 divergent promoter region, which is probably caused by the formation of a repressing H-NS-nucleoprotein complex.

Amino Acid Sequence↗
PubMed2006

A role of novel serpin maspin in tumor progression: the divergence revealed through efforts to converge.

Maspin, a 42 kDa protein, belongs to the serine protease inhibitor (serpin) superfamily and is more closely related to the ovalbumin-like serpin subfamily (ov-serpins). More than a decade after the discovery of the maspin gene, our pursuit of the molecular mechanisms of maspin revealed a significant divergence of maspin from other serpins. This review article summarizes recent advances in the identification of maspin-binding proteins and the potential underlying molecular mechanisms of maspin in tumor progression. Specifically, the molecular interactions of maspin with the cell surface-associated pro-urokinase-type plasminogen activator (pro-uPA) and intracellular histone deacetylase 1 (HDAC1) are highlighted. Our new evidence suggests a new paradigm that maspin acts as a serpin-like molecule to inhibit serine protease-like targets. From an evolution point of view, the uniquely important function of maspin in development and tumor progression is likely due to its ancestral sequence code, and accordingly, its novel "meta"-serpin structure. It is reasonable to hypothesize that the conservation of a serine protease-like catalytic center in many molecules requires the co-existence of endogenous antagonists. The unique inhibitory interaction of maspin with both HDAC1 and pro-uPA might not be substituted by other serpins that have evolved to acquire higher target specificities. Thus, tumor suppressive maspin offers a unique therapeutic opportunity.

Disease Progression↗
PubMed1980

Molecular evolution of mRNA: a method for estimating evolutionary rates of synonymous and amino acid substitutions from homologous nucleotide sequences and its application.

A method for estimating the evolutionary rates of synonymous and amino acid substitutions from homologous nucleotide sequences is presented. This method is applied to genes of phi X174 and G4 genomes, histone genes and beta-globin genes, for which homologous nucleotide sequences are available for comparison to be made. It is shown that the rates of synonymous substitutions are quite uniform among the non-overlapping genes of phi X174 and G4 and among histone genes H4, H2B, H3 and H2A. A comparison between phi X174 and G4 reveals that, in the overlapping segments of the A-gene, the rate of synonymous substitution is reduced more significantly than the rate of amino acid substitution relative to the corresponding rate in the non-overlapping segment. It is also suggested that, in the coding region surrounding the splicing points of intervening sequences of beta-globin genes, there exist rigid secondary structures. It is in only these regions that the beta-globin genes show the slowing down of evolutionary rates of both synonymous and amino acid substitutions in the primate line.

Amino Acid Sequence↗
PubMed2005

The hexosamine signaling pathway: deciphering the "O-GlcNAc code".

A dynamic cycle of addition and removal of O-linked N-acetylglucosamine (O-GlcNAc) at serine and threonine residues is emerging as a key regulator of nuclear and cytoplasmic protein activity. Like phosphorylation, protein O-GlcNAcylation dramatically alters the posttranslational fate and function of target proteins. Indeed, O-GlcNAcylation may compete with phosphorylation for certain Ser/Thr target sites. Like kinases and phosphatases, the enzymes of O-GlcNAc metabolism are highly compartmentalized and regulated. Yet, O-GlcNAc addition is subject to an additional and unique level of metabolic control. O-GlcNAc transfer is the terminal step in a "hexosamine signaling pathway" (HSP). In the HSP, levels of uridine 5'-diphosphate (UDP)-GlcNAc respond to nutrient excess to activate O-GlcNAcylation. Removal of O-GlcNAc may also be under similar metabolic regulation. Differentially targeted isoforms of the enzymes of O-GlcNAc metabolism allow the participation of O-GlcNAc in diverse intracellular functions. O-GlcNAc addition and removal are key to histone remodeling, transcription, proliferation, apoptosis, and proteasomal degradation. This nutrient-responsive signaling pathway also modulates important cellular pathways, including the insulin signaling cascade in animals and the gibberellin signaling pathway in plants. Alterations in O-GlcNAc metabolism are associated with various human diseases including diabetes mellitus and neurodegeneration. This review will focus on current approaches to deciphering the "O-GlcNAc code" in order to elucidate how O-GlcNAc participates in its diverse functions. This ongoing effort requires analysis of the enzymes of O-GlcNAc metabolism, their many targets, and how the O-GlcNAc modification may be regulated.

Acetylglucosamine↗
PubMed1986

A unique element resembling a processed pseudogene.

We describe a unique DNA element with structural features of a processed pseudogene but with important differences. It is located within an 8.4-kilobase pair region of chicken DNA containing five histone genes, but it is not related to these genes. The presence of terminal repeats, an open reading frame (and stop codon), polyadenylation/processing signal, and a poly(A) rich region about 20 bases 3' to this, together with a lack of 5' promoter motifs all suggest a processed pseudogene. However, no parent gene can be detected in the genome by Southern blotting experiments and, in addition, codon boundary values and mid-base correlations are not consistent with a protein coding region of a eukaryotic gene. The element was detected in DNA from different chickens and in peafowl, but not in quail, pheasant, or turkey.

Amino Acid Sequence↗
PubMed1984

Tetrahymena H4 genes: structure, evolution and organization in macro- and micronuclei.

The ciliated protozoan Tetrahymena thermophila contains two types of H4 histone genes (H4-I and H4-II). Southern blotting and analysis of DNA from nullisomic strains indicate that H4-I and H4-II are on different chromosomes and that only H4-II is closely linked to an H3 gene. No DNA sequence rearrangements are observed for either of the H4 genes when the transcriptionally inert, germ line, micronucleus is compared to the transcriptionally active, somatic macronucleus. Comparison of the H4-I gene and its flanking sequences to H4 gene sequences of other organisms indicates that there are evolutionary constraints on coding nucleotides that are unrelated to their protein coding function and that these evolutionary pressures operate at the level of translation.

Amino Acid Sequence↗
PubMed1985

Synthesis of sperm and late histone cDNAs of the sea urchin with a primer complementary to the conserved 3' terminal palindrome: evidence for tissue-specific and more general histone gene variants.

We have cloned histone cDNAs from total RNA isolated from testis and from gastrula-stage embryos of the sea urchin Psammechinus miliaris. The reverse transcription of histone mRNAs was specifically primed with an oligonucleotide that is complementary to the conserved palindromic sequence present at the 3' end of nonpolyadenylated histone mRNAs. Two sperm H2B, two late H2B, and three late H2A variant cDNA clones were isolated and characterized by DNA sequence analysis. These cDNA clones were used to study the accumulation of histone mRNA during sea urchin embryogenesis. The different late H2A and H2B mRNAs are present in as few as 200 copies in the egg and each accumulate to 3-5 X 10(5) molecules in the gastrula embryo. One of the late mRNAs, the H2A-3 mRNA, is also abundant in testis RNA and codes for the H2A variant present in sperm chromatin. The late H2A-3 protein is therefore a more prevalent H2A variant of the sea urchin. In contrast, the two sperm H2B mRNAs are found in testes but not ovaries and embryos of the sea urchin, suggesting that the sperm H2B genes are expressed only during spermatogenesis. In addition, evidence for gene conversion between two late H2A gene variants is presented.

Animals↗
PubMed1986

Periodic transcription as a means of regulating gene expression during the cell cycle: contrasting modes of expression of DNA ligase genes in budding and fission yeast.

Using cultures synchronised by three independent procedures, we have shown that the CDC9 gene, coding for DNA ligase, is periodically expressed in the Saccharomyces cerevisiae cell cycle. The level of CDC9 transcript increases many fold in late G1 reaching a peak at about the G1/S phase boundary and preceding the peak in histone message by some 20 min. The level of DNA ligase itself also fluctuates, showing the expected pattern for a stable enzyme synthesised periodically. In contrast, the transcript from the DNA ligase gene (CDC17) of Schizosaccharomyces pombe is present at a constant level throughout the cell cycle, and no fluctuation in amount was detected, although the histone H2A showed the expected periodic synthesis. Furthermore, DNA ligase activity remains at a constant level during the S. pombe cell cycle showing that there is unlikely to be any form of translational control. These contrasting modes of expression of the DNA ligase genes in the two organisms suggests that when periodic transcription is observed from an essential cell cycle gene, it may have no particular significance for regulating progress through the cell cycle. Also, regulatory circuits may be less well conserved between organisms than the processes they control and thus different organisms may utilise quite different modes of control to achieve the same ends.

Cell Cycle↗
PubMed2004

Kinetic profiles of p300 occupancy in vivo predict common features of promoter structure and coactivator recruitment.

Understanding the language encrypted in the gene regulatory regions of the human genome is a challenging goal for the genomic era. Although customary extrapolations from steady-state mRNA levels have been effective, deciphering these regulatory codes will require additional empirical data sets that more closely reflect the dynamic progression of molecular events responsible for inducible transcription. We describe an approach using chromatin immunoprecipitation to profile the kinetic occupancy of the transcriptional coactivator and histone acetyltransferase p300 at numerous mitogen-induced genes in activated T cells. Comparison of these profiles reveals a class of promoters that share common patterns of inducible expression, p300 recruitment, dependence on selective p300 domains, and sensitivity to histone deacetylase inhibitors. Remarkably, this class also shares an evolutionarily conserved promoter composition and structure that accurately predicts additional human genes with similar functional attributes. This "reverse genomic" approach will have broad application for the genome-wide classification of promoter structure and function.

Acetyltransferases↗
PubMed1991

Effect of the SV40 T antigen on the posttranscriptional regulation of the proliferating cell nuclear antigen and DNA polymerase-alpha genes.

tk-ts13 cells are G1-specific temperature-sensitive mutants of the cell cycle that arrest in G1 at the restrictive temperature. In these cells the mRNAs for early growth-regulated genes (for instance, c-myc) are inducible by serum at both permissive and restrictive temperatures. In contrast, the mRNAs for late growth-regulated genes [such as histones, proliferating cell nuclear antigen (PCNA), and DNA polymerase-alpha] are not detectable at the restrictive temperature, although they are normally induced by serum at the permissive temperature. Despite the absence of their mRNAs at the restrictive temperature, transcription rates for DNA polymerase-alpha, PCNA, and histone H3 are the same in serum-deprived cells and in cells that are serum stimulated at either the permissive or the restrictive temperature. Since the half-lives of the mRNAs are not substantially different at the two temperatures, the conclusion is that in tk-ts13 cells the mRNA levels of these late growth-regulated genes are regulated at a posttranscriptional level, presumably during hnRNA processing. When serum-deprived tk-ts13 cells carrying a stably integrated SV40 T antigen-coding gene (T-neo cells) are stimulated with serum, they are capable of one additional round of DNA replication at the restrictive temperature. At 20 h after stimulation of T-neo cells, the mRNAs for the late growth-regulated genes are detectable at the restrictive temperature in amounts not substantially different than those at the permissive temperature. Transcription rates in T-neo cells are increased for histone H3 (in comparison to tk-ts13 cells) but not for PCNA and DNA polymerase-alpha. The presence of the T antigen does not seem to seriously affect the half-lives of the mature mRNAs. The conclusion is that the presence of the SV40 T antigen in tk-ts13 cells promotes the appearance of mature mRNAs for DNA polymerase-alpha and PCNA. These experiments suggest that T antigen, in this instance, may intervene either directly or indirectly at a posttranscriptional level in the regulation of the steady state mRNA levels of certain cellular genes.

Animals↗
PubMed2004

Arresting cancer proliferation by small-molecule gene regulation.

A small library of pyrrole-imidazole polyamide-DNA alkylator (chlorambucil) conjugates was screened for effects on morphology and growth characteristics of a human colon carcinoma cell line, and a compound was identified that causes cells to arrest in the G2/M stage of the cell cycle. Microarray analysis indicates that the histone H4c gene is significantly downregulated by this polyamide. RT-PCR and Western blotting experiments confirm this result, and siRNA to H4c mRNA yields the same cellular response. Strikingly, reduction of H4 protein by >50% does not lead to widespread changes in global gene expression. Sequence-specific alkylation within the coding region of the H4c gene in cell culture was confirmed by LM-PCR. The compound is active in a wide range of cancer cell lines, and treated cells do not form tumors in nude mice. The compound is also active in vivo, blocking tumor growth in mice, without obvious animal toxicity.

Antineoplastic Agents, Alkylating↗
PubMed2005

Single chromatin fiber stretching reveals physically distinct populations of disassembly events.

Eukaryotic DNA is packaged into the cell nucleus as a nucleoprotein complex, chromatin. Despite this condensed state, access to the DNA sequence must occur during gene expression and other essential genetic events. Here we employ optical tweezers stretching of reconstituted chromatin fibers to investigate the release of DNA from its protein-bound structure. Analysis of fiber length increase per unbinding event revealed discrete values of approximately 30 and approximately 60 nm. Furthermore, a loading rate analysis of the disruption forces revealed three individual energy barriers. The heights of these barriers were found to be approximately 20 k(B)T, approximately 25 k(B)T, and approximately 28 k(B)T. For subsequent stretches of the fiber it was found that events corresponding to the approximately 28 k(B)T energy barrier were significantly reduced. No correlation between energy barrier crossed and DNA length release was found. These studies clearly demonstrate that optical tweezers stretching of chromatin provides insight into the energetic penalties imposed by chromatin structure. Furthermore these studies reveal possible pathways via which chromatin may be disrupted during genetic code access.

Animals↗