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Biomedical subjects

P Cartwright

Publications and source records attributed to P Cartwright.

At least 19 recordsLinked to original sources
PubMed2000

E2F family members are differentially regulated by reversible acetylation.

The six members of the E2F family of transcription factors play a key role in the control of cell cycle progression by regulating the expression of genes involved in DNA replication and cell proliferation. E2F-1, -2, and -3 belong to a structural and functional subfamily distinct from those of the other E2F family members. Here we report that E2F-1, -2, and -3, but not E2F-4, -5, and -6, associate with and are acetylated by p300 and cAMP-response element-binding protein acetyltransferases. Acetylation occurs at three conserved lysine residues located at the N-terminal boundary of their DNA binding domains. Acetylation of E2F-1 in vitro and in vivo markedly increases its binding affinity for a consensus E2F DNA-binding site, which is paralleled by enhanced transactivation of an E2F-responsive promoter. Acetylation of E2F-1 can be reversed by histone deacetylase-1, indicating that reversible acetylation is a mechanism for regulation also of non-histone proteins.

Acetylation↗
PubMed2000

Nucleocytoplasmic shuttling of transcription factors.

To elicit the transcriptional response following intra- or extracellular stimuli, the signals need to be transmitted to their site of action within the nucleus. The nucleocytoplasmic shuttling of transcription factors is a mechanism mediating this process. The activation and inactivation of the transcriptional response is essential for cells to progress through the cell cycle in a normal manner. The involvement of cytoplasmic and nuclear accessory molecules, and the general nuclear membrane transport components, are essential for this process. Although nuclear import and export for different transcription factor families are regulated by similar mechanisms, there are several differences that allow for the specific activation of each transcription factor. This review discusses the general import and export pathways found to be common amongst many different transcription factors, and highlights a select group of transcription factors that demonstrate the diversity displayed in their mode of activation and inactivation.

Animals↗
PubMed2000

Inverted papilloma of the urinary bladder in children: case report and review of prognostic significance and biological potential behavior.

Inverted papilloma of the urinary bladder is rare in the pediatric population. Despite several reports in the literature the prognostic significance and biological potential behavior of this lesion remain uncertain. The authors report a case of polypoid inverted papilloma of the urinary bladder in an 11-year-old boy and review its pathology. The pediatric population with this lesion is an ideal group to provide intense, long-term follow-up to define the biological behavior and prognosis significance of this lesion.

Child↗
PubMed1999

Colony integration and the expression of the Hox gene, Cnox-2, in Hydractinia symbiolongicarpus (Cnidaria: Hydrozoa).

The stolonal mat is an anatomical feature correlated with increased colonial integration in several lineages of the cnidarian class Hydrozoa. Cnox-2 is a Hox gene known to be expressed in the body column of the cnidarian polyp. We report the pattern of Cnox-2 expression in both the stolonal mat and free stolons of the hydroid Hydractinia symbiolongicarpus. The gene is found to have high levels of expression in the mat similar to that found in the basal portion of the polyp, but it is not detectably expressed in those regions of free stolons where polyps are budded. These findings suggest that the stolonal mat arose via an expansion of the basal ectoderm of the polyp.

Animals↗
PubMed1999

Expression of a Hox gene, Cnox-2, and the division of labor in a colonial hydroid.

We report the isolation and expression of the Hox gene, Cnox-2, in Hydractinia symbiolongicarpus, a hydrozoan displaying division of labor. We found different patterns of aboral-to-oral Cnox-2 expression among polyp polymorphs, and we show that experimental conversion of one polyp type to another is accompanied by concordant alteration in Cnox-2 expression. Our results are consistent with the suggestion that polyp polymorphism, characteristic of hydractiniid hydroids, arose via evolutionary modification of proportioning of head to body column.

Amino Acid Sequence↗
PubMed1999

CDC25A phosphatase is a target of E2F and is required for efficient E2F-induced S phase.

Functional inactivation of the pRB pathway is a very frequent event in human cancer, resulting in deregulated activity of the E2F transcription factors. To understand the functional role of the E2Fs in cell proliferation, we have developed cell lines expressing E2F-1, E2F-2, and E2F-3 fused to the estrogen receptor ligand binding domain (ER). In this study, we demonstrated that activation of all three E2Fs could relieve the mitogen requirement for entry into S phase in Rat1 fibroblasts and that E2F activity leads to a shortening of the G(0)-G(1) phase of the cell cycle by 6 to 7 h. In contrast to the current assumption that E2F-1 is the only E2F capable of inducing apoptosis, we showed that deregulated E2F-2 and E2F-3 activities also result in apoptosis. Using the ERE2F-expressing cell lines, we demonstrated that several genes containing E2F DNA binding sites are efficiently induced by the E2Fs in the absence of protein synthesis. Furthermore, CDC25A is defined as a novel E2F target whose expression can be directly regulated by E2F-1. Data showing that CDC25A is an essential target for E2F-1, since its activity is required for efficient induction of S phase by E2F-1, are provided. Finally, our results show that expression of two E2F target genes, namely CDC25A and cyclin E, is sufficient to induce entry into S phase in quiescent fibroblasts. Taken together, our results provide an important step in defining how E2F activity leads to deregulated proliferation.

Animals↗
PubMed1998

E2F-6: a novel member of the E2F family is an inhibitor of E2F-dependent transcription.

The E2F family of transcription factors are essential for the regulation of genes required for appropriate progression through the cell cycle. Five members of the E2F family have been previously reported, namely E2F1-5. All five are key elements in transcriptional regulation of essential genes, and they can be divided into two functional groups, those that induce S-phase progression when overexpressed in quiescent cells (E2Fs 1-3), and those that do not (E2Fs 4-5). Here, we describe the identification of a novel member of this family, which we refer to as E2F-6. E2F-6 shares significant homology with E2Fs 1-5, especially within the DNA binding, heterodimerization and marked box domains. Unlike E2Fs 1-5, E2F-6 lacks a transactivation and a pocket protein binding domain, hence, forms a unique third group within the E2F family. E2F-6 is a nuclear protein that can form heterodimers with the DP proteins (both DP-I and DP-2) in vitro and in vivo. Our results show that the complex formed between E2F-6 and the DP proteins, possesses high DNA binding activity, displaying a preference for a TTTCCCGC E2F recognition site, which is slightly different to the E2F consensus site derived from the E2 promoter (TTTCGCGC). In contrast to the other members of the E2F family, ectopic expression of E2F-6 inhibits transcription from promoters possessing E2F recognition sites rather than activating transcription. In addition, overexpression of E2F-6 suppresses the transactivational effects of coexpression of E2F-1 and DP-1. The inhibitory effect of E2F-6 is dependent on its DNA binding activity and its ability to form heterodimers with the DPs. Interestingly, ectopic expression of E2F-6 leads to accumulation of cells in S-phase. Our data suggest that E2F-6 expression delays the exit from S-phase rather than inducing S-phase, which further emphasizes the functional difference between E2F-6 and the previously known E2F family members.

Amino Acid Sequence↗
PubMed1997

The protein encoded by the MFT1 gene is a targeting factor for mitochondrial precursor proteins, and not a core ribosomal protein.

Yeast cells harboring mft1 mutations are compromised in mitochondrial protein targeting, and Mft1p has previously been identified as a ribosomal protein. However, two genes, PLC2 and YML062C, are present in the MFT1 locus, and we show that mft1 mutant cells are compromised in the function of the cytosolic protein encoded by YML062C. The ribosomal protein (YS3a) is actually encoded by the tightly linked PLC2 gene, and does not play a role in targeting proteins to the mitochondria.

Amino Acid Sequence↗
PubMed1997

Mft52, an acid-bristle protein in the cytosol that delivers precursor proteins to yeast mitochondria.

We have identified a novel protein, Mft52, in the cytosol of yeast cells. Mft52 has a two-domain structure that includes a receptor-like carboxyl-terminal "acid-bristle" domain, which binds basic, amphipathic mitochondrial targeting sequences. Native Mft52, purified from the cytosol of yeast cells, is found as a large particle eluting in the void volume of a Superose 6 gel filtration column. Fusion proteins, consisting of mitochondrial targeting sequences fused to nonmitochondrial passenger proteins, are targeted to mitochondria in wild-type yeast cells, but defects in the gene encoding Mft52 drastically reduce the delivery of these proteins to the mitochondria. We propose that Mft52 is a subunit of a particle that is part of a system of targeting factors and molecular chaperones mediating the earliest stages of protein targeting to the mitochondria.

Amino Acid Sequence↗
PubMed1996

Selective induction of mitochondrial chaperones in response to loss of the mitochondrial genome.

Molecular chaperones are known to play key roles in the synthesis, transport and folding of nuclear-encoded mitochondrial proteins and of proteins encoded by mitochondrial DNA. Although the regulation of heat-shock genes has been the subject of considerable investigation, regulation of the genes encoding mitochondrial chaperones is not well defined. We have found that stress applied specifically to the mitochondria of mammalian cells is capable of eliciting an organelle-specific, molecular chaperone response. Using the loss of mitochondrial DNA as a means of producing a specific mitochondrial stress, we show by Western-blot analysis that mtDNA-less (rho 0) rat hepatoma cells show an increase in the steady-state levels of chaperonin 60 (cpn 60) and chaperonin 10 (cpn 10). Nuclear transcription assays show that the upregulation of these chaperones is due to transcriptional activation. There was no effect on the inducible cytosolic Hsp 70, Hsp 72, nor on mtHsp 70 in rho 0 cells, leading us to concluded that stress applied selectively to mitochondria elicits a specific molecular chaperone response. Heat stress was able to provide an additional induction of cpn 60 and cpn 10 above that obtained for the rho 0 state alone, indicating that these genes have separate regulatory elements for the specific mitochondrial and general stress responses. Since the mitochondrial-specific chaperones are encoded by nuclear DNA, there must be a mechanism for molecular communication between the mitochondrion and nucleus and this system can address how stress is communicated between these organelles.

Animals↗
PubMed1995

An amino acid substitution in the pyruvate dehydrogenase E1 alpha gene, affecting mitochondrial import of the precursor protein.

A mutation in the mitochondrial targeting sequence was characterized in a male patient with X chromosome-linked pyruvate dehydrogenase E1 alpha deficiency. The mutation was a base substitution of G by C at nucleotide 134 in the mitochondrial targeting sequence of the PDHA1 gene, resulting in an arginine-to-proline substitution at codon 10 (R10P). Pyruvate dehydrogenase activity in cultured skin fibroblasts was 28% of the control value, and immunoblot analysis revealed a decreased level of pyruvate dehydrogenase E1 alpha immunoreactivity. Chimeric constructs in which the normal and mutant pyruvate dehydrogenase E1 alpha targeting sequences were attached to the mitochondrial matrix protein ornithine transcarbamylase were synthesized in a cell free translation system, and mitochondrial import of normal and mutant proteins was compared in vitro. The results show that ornithine transcarbamylase targeted by the mutant pyruvate dehydrogenase E1 alpha sequence was translocated into the mitochondrial matrix at a reduced rate, suggesting that defective import is responsible for the reduced pyruvate dehydrogenase level in mitochondria. The mutation was also present in an affected brother and the mildly affected mother. The clinical presentations of this X chromosome-linked disorder in affected family members are discussed. To our knowledge, this is the first report of an amino acid substitution in a mitochondrial targeting sequence resulting in a human genetic disease.

Amino Acids↗
PubMed1995

Breakpoint analysis: precise localization of genetic markers by means of nonstatistical computation using relatively few genotypes.

Placing new markers on a previously existing genetic map by using conventional methods of multilocus linkage analysis requires that a large number of reference families be genotyped. This paper presents a methodology for placing new markers on existing genetic maps by genotyping only a few individuals in a selected subset of the reference panel. We show that by identifying meiotic breakpoint events within existing genetic maps and genotyping individuals who exhibit these events, along with one nonrecombinant sibling and their parents, we can determine precise location for new markers even within subcentimorgan chromosomal regions. This method also improves detection of errors in genotyping and assists in the observation of chromosome behavior in specific regions.

Algorithms↗
PubMed1993

An Escherichia coli gene showing a potential ancestral relationship to the genes for the mitochondrial import site proteins ISP42 and MOM38.

An ORF (OrfT) of 1911 base pairs, upstream of the hip operon in Escherichia coli at map position 33.82 has been identified. The protein encoded by this sequence is predicted to have a molecular mass of 68,249 Da and the carboxyterminal 276 residues shows 26.8% and 25.4% identity with the import site proteins ISP42 and MOM38 from the mitochondrial outer membrane of Saccharomyces cerevisiae and Neurospora crassa, respectively. These mitochondrial membrane proteins have been shown to be essential components of the protein translocation apparatus in yeast. These similarities raise the possibility that OrfT might represent the bacterial gene from which these eukaryotic genes evolved.

Amino Acid Sequence↗
PubMed1993

HOM/Hox type homeoboxes in the chelicerate Limulus polyphemus.

The polymerase chain reaction was used to survey HOM/Hox type homeobox genes in the North American horseshoe crab, Limulus polyphemus. The survey reveals 28 different homeobox fragments possessing 44-80% nucleotide sequence similarity with HOM-C sequences in Drosophila and Hox B sequences in mouse. Limulus has one to four representatives of HOM/Hox cognates when fragments are assigned according to amino acid identity. A parsimony analysis including the Limulus sequences and homologous mouse Hox B and Drosophila HOM-C sequences reveals several instances of monophyletic groupings of Limulus homeoboxes with a Drosophila or mouse gene as the sister branch. Under the current model of HOM/Hox cluster evolution, these results suggest that Limulus has as many as four HOM/Hox type clusters. This is the first evidence suggesting the presence of multiple clusters in a nonvertebrate taxon. Putative homologs of mouse Hoxb-3 in Limulus suggest that the gene was present in the common ancestor of arthropods and vertebrates and has been lost in Drosophila.

Amino Acid Sequence↗
PubMed1991

Chromosomal mapping of two genetic loci associated with blood-pressure regulation in hereditary hypertensive rats.

The spontaneously hypertensive rat and the stroke-prone spontaneously hypertensive rat are useful models for human hypertension. In these strains hypertension is a polygenic trait, in which both autosomal and sex-linked genes can influence blood pressure. Linkage studies in crosses between the stroke-prone spontaneously hypertensive rat and the normotensive control strain Wistar-Kyoto have led to the localization of two genes, BP/SP-1 and BP/SP-2, that contribute significantly to blood pressure variation in the F2 population. BP/SP-1 and BP/SP-2 were assigned to rat chromosomes 10 and X, respectively. Comparison of the human and rat genetic maps indicates that BP/SP-1 could reside on human chromosome 17q in a region that also contains the angiotensin I-converting enzyme gene (ACE). This encodes a key enzyme of the renin-angiotensin system, and is therefore a candidate gene in primary hypertension. A rat microsatellite marker of ACE was mapped to rat chromosome 10 within the region containing BP/SP-1.

Animals↗