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1.
Cancer Res ; 61(19): 7255-63, 2001 Oct 01.
Article in English | MEDLINE | ID: mdl-11585763

ABSTRACT

Prostate cancer cells are generally resistant to apoptosis by conventional therapy. During a search for molecules that may overcome prostate cancer cell survival mechanisms, we identified the prostate apoptosis response-4 (Par-4) gene. Par-4 induced apoptosis of selective prostate cancer cells PC-3, DU-145, and TSU-Pr and caused tumor regression by inhibition of NF-kappaB activity and cell membrane trafficking of Fas and FasL that leads to the activation of the Fas-Fas-associated death domain-caspase-8 pro-death pathway. Neither Fas pathway activation alone nor inhibition of NF-kappaB activity with IkappaB-super repressor was sufficient to induce apoptosis of prostate cancer cells. Coregulation of these two pathways was essential and sufficient for Par-4 to induce apoptosis. On the other hand, prostate cancer cells LNCaP or normal prostatic epithelial cells that were resistant to apoptosis by Par-4 did not show Fas or FasL trafficking. These findings identify a mechanism of apoptosis by Par-4 and suggest that Par-4 may have therapeutic potential.


Subject(s)
Apoptosis/physiology , Carrier Proteins/physiology , Intracellular Signaling Peptides and Proteins , Membrane Glycoproteins/physiology , Prostatic Neoplasms/pathology , Tumor Suppressor Proteins , fas Receptor/physiology , Androgens/physiology , Animals , Apoptosis/genetics , Apoptosis Regulatory Proteins , Carrier Proteins/antagonists & inhibitors , Carrier Proteins/genetics , Cell Membrane/metabolism , Fas Ligand Protein , Humans , Male , Membrane Glycoproteins/metabolism , Mice , NF-kappa B/antagonists & inhibitors , NF-kappa B/physiology , Neoplasms, Hormone-Dependent/genetics , Neoplasms, Hormone-Dependent/pathology , PTEN Phosphohydrolase , Phosphoric Monoester Hydrolases/antagonists & inhibitors , Phosphoric Monoester Hydrolases/genetics , Phosphoric Monoester Hydrolases/physiology , Prostatic Neoplasms/genetics , Prostatic Neoplasms/therapy , Proto-Oncogene Proteins c-bcl-2/physiology , Signal Transduction/physiology , Transcription, Genetic/physiology , Transfection , Tumor Suppressor Protein p53/physiology , Xenograft Model Antitumor Assays , bcl-X Protein , fas Receptor/metabolism
2.
Oncogene ; 18(50): 7115-23, 1999 Nov 25.
Article in English | MEDLINE | ID: mdl-10597313

ABSTRACT

Oncogenic variants of the cellular Ras protein are often associated with different types of human cancers. However, the mechanisms by which oncogenic Ras induces transformation are not fully established. Expression of the transcriptional repressor Par-4 was down-regulated by oncogenic Ras via the Raf-MEK-ERK pathway. Restoration of Par-4 levels by abrogation of the Raf-MEK-ERK pathway with the MEK-inhibitor PD98059 or by ectopic Par-4, that acted to inhibit ERK expression and activation, was sufficient to suppress oncogenic Ras-induced transformation. These findings identify Par-4 as a novel target that has to be down-modulated by oncogenic Ras for successful transformation.


Subject(s)
Carrier Proteins/genetics , Cell Transformation, Neoplastic/genetics , Down-Regulation/physiology , Intracellular Signaling Peptides and Proteins , Proto-Oncogene Proteins p21(ras)/physiology , 3T3 Cells , Animals , Apoptosis Regulatory Proteins , Flavonoids/pharmacology , Humans , Mice
3.
J Biol Chem ; 274(42): 29976-83, 1999 Oct 15.
Article in English | MEDLINE | ID: mdl-10514481

ABSTRACT

Certain mutations in the mammalian ras gene are oncogenic and are often detected in human cancers. Oncogenic Ras induces the transcription activity of NF-kappaB that confers cell survival. Oncogenic Ras also down-modulates the expression of Par-4, a transcriptional repressor protein, that is essential but not sufficient on its own to induce apoptosis. Here we show that reintroduction of Par-4 by transient transfection leads to apoptosis in cells expressing oncogenic Ras but not in those that lack oncogenic Ras expression. Par-4 abrogates oncogenic Ras-inducible NF-kappaB transcription activity but does not interfere with cytoplasmic activation, or the DNA binding activity, of NF-kappaB. Because abrogation of NF-kappaB transcription activity is sufficient to cause apoptosis in cells expressing oncogenic Ras, our findings identify Par-4 as a novel example of a pro-apoptotic protein that selectively inhibits oncogenic Ras-dependent NF-kappaB function at the transcription level and suggest a mechanism by which Par-4 expression may selectively induce apoptosis in oncogenic Ras-expressing cells.


Subject(s)
Apoptosis/physiology , Carrier Proteins/physiology , I-kappa B Proteins , Intracellular Signaling Peptides and Proteins , Oncogene Protein p21(ras)/physiology , 3T3 Cells , Animals , Apoptosis Regulatory Proteins , DNA/metabolism , DNA-Binding Proteins/metabolism , Humans , Hydrolysis , Ligases/antagonists & inhibitors , Ligases/metabolism , Mice , NF-KappaB Inhibitor alpha , NF-kappa B/antagonists & inhibitors , NF-kappa B/metabolism , Proto-Oncogene Proteins c-raf/metabolism , Transcription, Genetic
4.
Virology ; 236(2): 296-306, 1997 Sep 29.
Article in English | MEDLINE | ID: mdl-9325237

ABSTRACT

The subcellular locations of two potyviral proteins, the coat (CP) and nonstructural cylindrical inclusion (CI) proteins of tobacco vein mottling virus (TVMV), during early stages in the development of systemic infections in plants, have been investigated. Ultrathin sections of newly emerged leaves in infected plants were treated with antibodies specific to these proteins and then with gold-labeled secondary antibodies and examined by electron microscopy. CI was detected near plasmodesmatal connections between mesophyll cells prior to the appearance of CP or any virus-induced features or effects. Further accumulation of CI was evident in the form of conical structures, many of which appeared to penetrate the cell wall and to be connected to cones in neighboring cells. Prior to its appearance in other parts of the cells, the viral CP was detected, often in linear arrays, near the vertices or inside the cones and in plasmodesmata. In situ hybridization analysis of similar tissue sections with a TVMV RNA-specific oligoribonucleotide probe revealed the presence of the viral RNA in plasmodesmata. These results lend support to the notion that the formation of specific structures by potyviral CI proteins is required for and plays a direct role in the intercellular passage of viral genetic material, in the form of virus particles or complexes containing viral CP and RNA, in infected plants.


Subject(s)
Capsid/physiology , Inclusion Bodies, Viral/physiology , Nicotiana/virology , Plants, Toxic , Potyvirus/physiology , Potyvirus/pathogenicity , Viral Proteins/physiology , Cell Membrane/ultrastructure , Cell Membrane/virology , In Situ Hybridization , Inclusion Bodies, Viral/ultrastructure , Intercellular Junctions/virology , Microscopy, Immunoelectron , Plant Diseases/virology , Potyvirus/genetics , RNA, Viral/genetics , RNA, Viral/metabolism , Nicotiana/ultrastructure
5.
Virology ; 227(1): 180-8, 1997 Jan 06.
Article in English | MEDLINE | ID: mdl-9007071

ABSTRACT

Gene II of cauliflower mosaic virus (CaMV), which encodes an 18-kDa protein originally identified as an aphid transmission factor (ATF), influences host specificity in a light-dependent manner. A point mutation within the ATF gene that occurs in several CaMV strains was responsible for conditioning light-dependent systemic infections. A point mutant of CaMV strain W260 that carried the single mutation within the ATF gene was able to systemically infect Nicotiana bigelovii at low light intensity (100-180 micromol m-2 sec-1), but not at a higher light intensity level (350-450 micromol m-2 sec-1), while the wild-type W260 virus could systemically infect N. bigelovii under both light conditions. The same point mutation also affected the stability of the amorphous CaMV inclusions and previous studies have shown that it abolishes transmission of CaMV by aphids. The point mutation within the ATF gene that mediated light-dependent infections was complemented by transgenic N. bigelovii plants that express the CaMV gene VI product, a viral protein that has been identified as a translational transactivator. The complementation studies indicated that the ATF gene may influence systemic infections through an interaction with the CaMV gene VI product. The ATF gene of CaMV may contribute to viral infections by regulating expression of downstream genes or by influencing cell-to-cell or long distance movement within the plant.


Subject(s)
Caulimovirus/genetics , Caulimovirus/radiation effects , Light , Nicotiana/virology , Plants, Toxic , Viral Nonstructural Proteins/genetics , Animals , Aphids , Caulimovirus/physiology , Genetic Complementation Test , Inclusion Bodies, Viral/genetics , Plant Diseases/virology , Point Mutation , Regulatory Sequences, Nucleic Acid , Trans-Activators/genetics , Viral Proteins/genetics
6.
Virology ; 190(2): 773-82, 1992 Oct.
Article in English | MEDLINE | ID: mdl-1519358

ABSTRACT

We have identified regions of CaMV strain W260 involved in systemic infection of Nicotiana bigelovii and Datura stramonium by constructing chimeric viruses between W260 and CM1841, a strain that is unable to systemically infect any solanaceous host. All of the chimeric viruses systemically infected turnips, demonstrating the viability of the chimeric viruses in a host that is susceptible to both CM1841 and W260. Three regions of W260, containing primarily genes I, IV, and VI, influenced the ability of that virus to induce systemic symptoms in the solanaceous hosts. The involvement of the regions containing gene I, and to a lesser extent gene IV, were affected by environmental conditions. When infected plants were grown under conditions of low light, low temperatures (18 degrees), and short days (9.5-hr day), the source of genes I and IV no longer influenced whether a chimeric virus moved systemically. As light intensity and day length were increased, the genetic requirements became more stringent and genes I and IV, as well as gene VI, had to be derived from W260.


Subject(s)
Genes, Viral/genetics , Mosaic Viruses/genetics , Plants/microbiology , Amino Acid Sequence , Base Sequence , Enzyme-Linked Immunosorbent Assay , Molecular Sequence Data , Mosaic Viruses/chemistry , Mosaic Viruses/pathogenicity , Temperature
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