ABSTRACT
The family of tumor necrosis factor related apoptosis inducing ligand (TRAIL) receptors, including the pro-apoptotic DR4 and p53-regulated KILLER/DR5, as well as the decoys TRID and TRUNDD, are all located on human chromosome 8p21-22. This region of the genome is frequently altered in head and neck cancer. We previously reported that KILLER/DR5 can be mutationally inactivated in head and neck cancer. Here, we report that the FaDu nasopharyngeal cancer cell line contains an abnormal chromosome 8p21-22 region. In addition, there appears to be a homozygous deletion involving DR4 but not KILLER/DR5 in FaDu cells. The homozygous loss within the DR4 gene encompasses its death domain, which is required for apoptotic signaling. The deletion of DR4 in FaDu cells is associated with resistance to the cytotoxic effects of TRAIL. Re-introduction of wild-type DR4 leads to apoptosis and restores TRAIL sensitivity of FaDu cells. These observations suggest that the death inducing DR4 receptor gene may be a rare target for inactivation in human cancer and that DR4 loss may contribute to resistance to TRAIL therapy.
Subject(s)
Gene Deletion , Nasopharyngeal Neoplasms/genetics , Receptors, Tumor Necrosis Factor/genetics , Apoptosis , Chromosomes, Human, Pair 8 , Humans , Loss of Heterozygosity , Microsatellite Repeats , Receptors, TNF-Related Apoptosis-Inducing Ligand , Tumor Cells, CulturedABSTRACT
The breast and ovarian cancer susceptibility gene product BRCA1 has been reported to be expressed in a cell cycle-dependent manner; possess transcriptional activity; associate with several proteins, including the p53 tumor suppressor; and play an integral role in certain types of DNA repair. We show here that ectopic expression of BRCA1 using an adenovirus vector (Ad-BRCA1) leads to dephosphorylation of the retinoblastoma protein accompanied by a decrease in cyclin-dependent kinase activity. Flow cytometric analysis on Ad-BRCA1-infected cells revealed a G(1) or G(2) phase accumulation. High density cDNA array screening of colon, lung, and breast cancer cells identified several genes affected by BRCA1 expression in a p53-independent manner, including DNA damage response genes and genes involved in cell cycle control. Notable changes included induction of the GADD45 and GADD153 genes and a reduction in cyclin B1 expression. Therefore, BRCA1 has the potential to modulate the expression of genes and function of proteins involved in cell cycle control and DNA damage response pathways.
Subject(s)
BRCA1 Protein/physiology , CCAAT-Enhancer-Binding Proteins , CDC2-CDC28 Kinases , Cell Cycle/physiology , DNA Damage , Gene Expression/physiology , Proto-Oncogene Proteins c-bcl-2 , Adenoviridae/genetics , BRCA1 Protein/genetics , Cyclin-Dependent Kinase 2 , Cyclin-Dependent Kinases/antagonists & inhibitors , DNA-Binding Proteins/genetics , Humans , Intracellular Signaling Peptides and Proteins , NIMA-Interacting Peptidylprolyl Isomerase , Peptidylprolyl Isomerase/genetics , Phosphorylation , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proteins/genetics , Proto-Oncogene Proteins/genetics , Retinoblastoma Protein/metabolism , Transcription Factor CHOP , Transcription Factors/genetics , Tumor Cells, Cultured , bcl-2-Associated X Protein , GADD45 ProteinsABSTRACT
We report our initial experience with thoracoscopic surgery in the treatment of spontaneous pneumothorax in 14 patients, mean age 30.7 years. 7 were operated following 2 episodes of spontaneous pneumothorax, 6 after their first episode, and 1 after multiple episodes. All underwent bleb resection, pleurodesis and tube thoracostomy; in 1 we converted to a limited thoracotomy (93% success rate). Only oral analgesia was required for postoperative pain control and patients were discharged 2.6 days after surgery, on average. The apparent superiority of thoracoscopic over conventional, even limited, thoracotomy seems to justify such therapy even during the first episode.
Subject(s)
Pneumothorax/surgery , Thoracic Surgery, Video-Assisted , Adult , Aged , Female , Humans , Male , Middle Aged , Pain, Postoperative , Retrospective Studies , Treatment OutcomeABSTRACT
Neuropeptide Y (NPY) receptors belong to the G-protein-coupled receptor (GPCR) superfamily and mediate several physiological responses, such as blood pressure, food intake, sedation and memory retention. To understand the interactions between the NPY Y1 receptor subtype and its ligands, computer modeling was applied to the natural peptide agonist, NPY and a small molecule antagonist, BIBP3226. An agonist and antagonist binding domain was elucidated using mutagenesis data for the Y1 receptor as well as for other GPCR families. The agonist and antagonist ligands which were investigated appear to share common residues for their interaction within the transmembrane regions of the Y1 receptor structure, including Gln120, Asn283 and His306. This is in contrast to findings with tachykinin receptors where the binding domains of the non-peptide antagonists have very little in common with the binding domains of the agonist, substance-P. In addition, a hydrogen bond between the hydroxyl group of Tyr36 of NPY and the side chain of Gln219, an interaction that is absent in the model complex between Y1 and the antagonist BIBP3226, is proposed as one of the potential interactions necessary for receptor activation.
