Abstract:
:Programmed cell death (apoptosis) is a normal physiological process, which could in principle be manipulated to play an important role in cancer therapy. The key importance of p53 expression in the apoptotic response to DNA-damaging agents has been stressed because mutant or deleted p53 is so common in most kinds of cancer. An important strategy, therefore, is to find ways to induce apoptosis in the absence of wild-type p53. In this paper, we compare apoptosis in normal human mammary epithelial cells, in cells immortalized with human papilloma virus (HPV), and in mammary carcinoma cell lines expressing wild-type p53, mutant p53, or no p53 protein. Apoptosis was induced with mitomycin C (MMC), a DNA cross-linking and damaging agent, or with staurosporine (SSP), a protein kinase inhibitor. The normal and HPV-transfected cells responded more strongly to SSP than did the tumor cells. After exposure to MMC, cells expressing wild-type p53 underwent extensive apoptosis, whereas cells carrying mutated p53 responded weakly. Primary breast cancer cell lines null for p53 protein were resistant to MMC. In contrast, two HPV immortalized cell lines in which p53 protein was destroyed by E6-modulated ubiquitinylation were highly sensitive to apoptosis induced by MMC. Neither p53 mRNA nor protein was induced in the HPV immortalized cells after MMC treatment, although p53 protein was elevated by MMC in cells with wild-type p53. Importantly, MMC induced p21 mRNA but not p21 protein expression in the HPV immortalized cells. Thus, HPV 16E6 can sensitize mammary epithelial cells to MMC-induced apoptosis via a p53- and p21-independent pathway. We propose that the HPV 16E6 protein modulates ubiquitin-mediated degradation not only of p53 but also of p21 and perhaps other proteins involved in apoptosis.
journal_name
Proc Natl Acad Sci U S Aauthors
Xu C,Meikrantz W,Schlegel R,Sager Rdoi
10.1073/pnas.92.17.7829subject
Has Abstractpub_date
1995-08-15 00:00:00pages
7829-33issue
17eissn
0027-8424issn
1091-6490journal_volume
92pub_type
杂志文章abstract::The recent emergence and reemergence of viruses in the human population has highlighted the need to develop broader panels of therapeutic molecules. High-throughput screening assays opening access to untargeted steps of the viral replication cycle will provide powerful leverage to identify innovative antiviral molecul...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.2010524118
更新日期:2021-01-12 00:00:00
abstract::Invariant natural killer T cell (NKT) cells (iNKT cells) produce both T-helper 1 (Th1) and T-helper 2 cytokines in response to α-Galactosylceramide (α-GalCer) stimulation and are thought to be the important effectors in the regulation of both innate and adaptive immunity involved in autoimmune disorders, microbial inf...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1114255108
更新日期:2011-10-18 00:00:00
abstract::Osteogenin was recently purified and the amino acid sequences of tryptic peptides were determined. Osteogenin in conjunction with insoluble collagenous bone matrix induces cartilage and bone formation in vivo. To understand the mechanism of action of osteogenin, we examined its influence on periosteal cells, osteoblas...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.86.22.8793
更新日期:1989-11-01 00:00:00
abstract::We introduce and analyze a general model of a population evolving over a network of selectively neutral genotypes. We show that the population's limit distribution on the neutral network is solely determined by the network topology and given by the principal eigenvector of the network's adjacency matrix. Moreover, the...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.96.17.9716
更新日期:1999-08-17 00:00:00
abstract::The concept of a charge density wave (CDW) permeates much of condensed matter physics and chemistry. CDWs have their origin rooted in the instability of a one-dimensional system described by Peierls. The extension of this concept to reduced dimensional systems has led to the concept of Fermi surface nesting (FSN), whi...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1424791112
更新日期:2015-02-24 00:00:00
abstract::Animal development is remarkably robust; cell fates are specified with spatial and temporal precision despite physiological and environmental contingencies. Favorable conditions cause Caenorhabditis elegans to develop rapidly through four larval stages (L1-L4) to the reproductive adult. In unfavorable conditions, L2 l...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0908131106
更新日期:2009-11-03 00:00:00
abstract::We have found the two-dimensional electrophoretic technique of O'Farrell to be highly efficient in the detection of charge-change substitutions in a large number of proteins. We have applied this method to determine the level of heterozygosity of the most abundant proteins in Drosophila melanogaster adults from a natu...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.76.5.2381
更新日期:1979-05-01 00:00:00
abstract::An unusual cAMP signaling system mediates many of the events that prepare spermatozoa to meet the egg. Its components include the atypical, bicarbonate-stimulated, sperm adenylyl cyclase and a cAMP-dependent protein kinase (PKA) with the unique catalytic subunit termed Calpha(2) or C(s). We generated mice that lack Ca...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0405580101
更新日期:2004-09-14 00:00:00
abstract::Streptococcus pneumoniae can cause disease in various human tissues and organs, including the ear, the brain, the blood, and the lung, and thus in highly diverse and dynamic environments. It is challenging to study how pneumococci control virulence factor expression, because cues of natural environments and the presen...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1920015117
更新日期:2020-11-03 00:00:00
abstract::We have identified new genomic alterations in the breast cancer cell line HCC1954, using high-throughput transcriptome sequencing. With 120 Mb of cDNA sequences, we were able to identify genomic rearrangement events leading to fusions or truncations of genes including MRE11 and NSD1, genes already implicated in oncoge...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0812945106
更新日期:2009-02-10 00:00:00
abstract::The synthesis of cytoplasmic proteins from quiescent and serum-stimulated Swiss 3T3 cells was compared by two-dimensional polyacrylamide gel electrophoresis. Four new proteins of Mrs 26,000, 28,000, 45,000, and 47,000 designated N26, N28, N45, and N47, which were not detectable in quiescent cells, appeared 60 min afte...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.78.9.5712
更新日期:1981-09-01 00:00:00
abstract::Vacuoles are essential organelles in plants, playing crucial roles, such as cellular material degradation, ion and metabolite storage, and turgor maintenance. Vacuoles receive material via the endocytic, secretory, and autophagic pathways. Membrane fusion is the last step during which prevacuolar compartments (PVCs) a...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1905321116
更新日期:2019-10-15 00:00:00
abstract::Type I and type III IFNs bind to different cell-surface receptors but induce identical signal transduction pathways, leading to the expression of antiviral host effector molecules. Despite the fact that type III IFN (IFN-λ) has been shown to predominantly act on mucosal organs, in vivo infection studies have failed to...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1100552108
更新日期:2011-05-10 00:00:00
abstract::The multisubunit vacuolar-type H(+)ATPases mediate acidification of various intracellular organelles and in some tissues mediate H(+) secretion across the plasma membrane. Mutations in the B1-subunit of the apical H(+)ATPase that secretes protons in the distal nephron cause distal renal tubular acidosis in humans, a c...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0506769102
更新日期:2005-09-20 00:00:00
abstract::It is widely accepted that the heavily glycosylated glycoprotein gp120 on the surface of HIV-1 shields peptide epitopes from recognition by the immune system and may promote infection in vivo by interaction with dendritic cells and transport to tissue rich in CD4(+) T cells such as lymph nodes. A conserved cluster of ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0712326105
更新日期:2008-03-11 00:00:00
abstract::We have identified the mutation responsible for the autosomal recessive wasted (wst) mutation of the mouse. Wasted mice are characterized by wasting and neurological and immunological abnormalities starting at 21 days after birth; they die by 28 days. A deletion of 15.8 kb in wasted mice abolishes expression of a gene...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.95.8.4463
更新日期:1998-04-14 00:00:00
abstract::Colocalization of proteins that are part of the same signal transduction pathway via compartmentalization, scaffold, or anchor proteins is an essential aspect of the signal transduction system in eukaryotic cells. If interaction must occur via free diffusion, then the spatial separation between the sources of the two ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0401314101
更新日期:2004-04-27 00:00:00
abstract::Endogenous circadian rhythms have been described in a wide range of organisms from prokaryotes to man. Although basic circadian mechanisms at the molecular level are genetically fixed, certain properties of circadian rhythms at the organismic level can be modified by environmental conditions and subsequently retained ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.200354997
更新日期:2000-10-24 00:00:00
abstract::The polyamines, putrescine, spermidine, and spermine, are essential polycations, intimately involved in the regulation of cellular proliferation. Although polyamines exert dynamic effects on the conformation of nucleic acids and macromolecular synthesis in vitro, their specific functions in vivo are poorly understood....
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1219002110
更新日期:2013-02-05 00:00:00
abstract::The mammalian hair follicle unit consists of a central follicle and a series of associated structures: sebaceous glands, arrector pili muscles, Merkel cells, and sensory nerve endings. The architecture of this multicellular structure is highly polarized with respect to the body axes. Previous work has implicated Frizz...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1301430110
更新日期:2013-03-05 00:00:00
abstract::The Golgi apparatus is a membrane-bounded organelle with the characteristic shape of a series of stacked flat cisternae. During mitosis in mammalian cells, the Golgi apparatus is once fragmented into small vesicles and then reassembled to form the characteristic shape again in each daughter cell. The mechanism and det...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1619264114
更新日期:2017-05-16 00:00:00
abstract::Saccharomyces cerevisiae strains expressing the activated RAS2Val19 gene or lacking both cAMP phosphodiesterase genes, PDE1 and PDE2, have impaired growth control and display an acute sensitivity to heat shock. We have isolated two classes of mammalian cDNAs from yeast expression libraries that suppress the heat shock...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.88.7.2913
更新日期:1991-04-01 00:00:00
abstract::Nitroxyl anion (HNONO(-)), the one-electron reduced form of nitric oxide (NO), induces positive cardiac inotropy and selective venodilation in the normal in vivo circulation. Here we tested whether HNO/NO(-) augments systolic and diastolic function of failing hearts, and whether contrary to NO/nitrates such modulation...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0937302100
更新日期:2003-04-29 00:00:00
abstract::The first step in the replication of the adenovirus genome is the covalent attachment of the 5'-terminal nucleotide, dCMP, to the virus-encoded terminal protein precursor (pTP). This reaction can be observed in vitro and has been previously shown to be dependent upon either viral DNA or linearized plasmid DNA containi...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.81.1.100
更新日期:1984-01-01 00:00:00
abstract::The regional structure of fibrinogen was considered in reference to the terminal plasmin-cleavage fragments, D and E. By two independent approaches, a yield of two D and two E fragments was determined and this established the presence of two D and two E regions in each fibrinogen molecule. Immunochemically, it was sho...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.71.1.158
更新日期:1974-01-01 00:00:00
abstract::O-GlcNAc glycosylation (or O-GlcNAcylation) is a dynamic, inducible posttranslational modification found on proteins associated with neurodegenerative diseases such as α-synuclein, amyloid precursor protein, and tau. Deletion of the O-GlcNAc transferase (ogt) gene responsible for the modification causes early postnata...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1606899113
更新日期:2016-12-27 00:00:00
abstract::Human capabilities in manipulating many different tools with dexterity suggest modular neural organization at functional levels, but anatomical modularity underlying the capabilities has yet to be demonstrated. Although modularity in phylogenetically older parts of the cerebellum is well known, comparable modularity i...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0835746100
更新日期:2003-04-29 00:00:00
abstract::The mechanism by which mammalian cells acquire resistance to chemotherapeutic agents has been investigated by using molecular genetic techniques. LZ and C5, two independently derived multidrug-resistant Chinese hamster cell lines, share specific amplified DNA sequences. We demonstrate that commonly amplified DNA seque...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.83.2.337
更新日期:1986-01-01 00:00:00
abstract::Genome-wide association studies found that increased risk for atrial fibrillation (AF), the most common human heart arrhythmia, is associated with noncoding sequence variants located in proximity to PITX2 Cardiomyocyte-specific epigenomic and comparative genomics uncovered 2 AF-associated enhancers neighboring PITX2 w...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1907418116
更新日期:2019-11-05 00:00:00
abstract::RNA interference, mediated by small interfering RNAs (siRNAs), is a conserved regulatory process that has evolved as an antiviral defense mechanism in plants and animals. It is not known whether host cells also use siRNAs as an antibacterial defense mechanism in eukaryotes. Here, we report the discovery of an endogeno...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0608258103
更新日期:2006-11-21 00:00:00