Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 2 de 2
Filter
Add more filters










Database
Language
Publication year range
1.
J Clin Oncol ; 22(14): 2954-63, 2004 Jul 15.
Article in English | MEDLINE | ID: mdl-15254063

ABSTRACT

Genetic alterations targeting the PTEN tumor suppressor gene are among the most frequently noted somatic mutations in human cancers. Such lesions have been noted in cancers of the prostate and endometrium and in glioblastoma multiforme, among many others. Moreover, germline mutation of PTEN leads to the development of the related hereditary cancer predisposition syndromes, Cowden disease, and Bannayan-Zonana syndrome, wherein breast and thyroid cancer incidence is elevated. The protein product, PTEN, is a lipid phosphatase, the enzymatic activity of which primarily serves to remove phosphate groups from key intracellular phosphoinositide signaling molecules. This activity normally serves to restrict growth and survival signals by limiting activity of the phosphoinositide-3 kinase (PI3K) pathway. Multiple lines of evidence support the notion that this function is critical to the ability of PTEN to maintain cell homeostasis. Indeed, the absence of functional PTEN in cancer cells leads to constitutive activation of downstream components of the PI3K pathway including the Akt and mTOR kinases. In model organisms, inactivation of these kinases can reverse the effects of PTEN loss. These data raise the possibility that drugs targeting these kinases, or PI3K itself, might have significant therapeutic activity in PTEN-null cancers. Akt kinase inhibitors are still in development; however, as a first test of this hypothesis, phase I and phase II trials of inhibitors of mTOR, namely, rapamycin and rapamycin analogs are underway.


Subject(s)
Genes, Tumor Suppressor/physiology , Neoplasms/genetics , Phosphoric Monoester Hydrolases/physiology , Protein Kinases , Signal Transduction/physiology , Tumor Suppressor Proteins/physiology , Antineoplastic Agents/therapeutic use , Cell Transformation, Neoplastic/genetics , Genetic Predisposition to Disease/genetics , Humans , Mutation/genetics , Neoplasms/drug therapy , Neoplasms/physiopathology , PTEN Phosphohydrolase , Phosphatidylinositol 3-Kinases/physiology , Phosphoric Monoester Hydrolases/genetics , Protein Kinase Inhibitors , TOR Serine-Threonine Kinases , Tumor Suppressor Proteins/genetics
2.
Cancer Cell ; 2(1): 81-91, 2002 Jul.
Article in English | MEDLINE | ID: mdl-12150827

ABSTRACT

The mammalian DAF-16-like transcription factors, FKHR, FKHRL1, and AFX, function as key regulators of insulin signaling, cell cycle progression, and apoptosis downstream of phosphoinositide 3-kinase. Gene activation through binding to insulin response sequences (IRS) has been thought to be essential for mediating these functions. However, using transcriptional profiling, chromatin immunoprecipitation, and functional experiments, we demonstrate that rather than activation of IRS regulated genes (Class I transcripts), transcriptional repression of D-type cyclins (in Class III) is required for FKHR mediated inhibition of cell cycle progression and transformation. These data suggest that a novel mechanism of FKHR-mediated gene regulation is linked to its activity as a suppressor of tumor growth.


Subject(s)
DNA-Binding Proteins/genetics , DNA-Binding Proteins/physiology , Gene Expression Regulation, Neoplastic , Genes, Tumor Suppressor , Protein Serine-Threonine Kinases , Transcription Factors/genetics , Transcription Factors/physiology , Adenoviridae/genetics , Carcinoma/pathology , Cell Cycle/physiology , Cell Line , Cyclins/genetics , Cyclins/physiology , Down-Regulation , Forkhead Box Protein O1 , Forkhead Box Protein O3 , Forkhead Transcription Factors , Gene Expression Profiling , Glioblastoma/pathology , Humans , Kidney Neoplasms/pathology , Kinetics , PTEN Phosphohydrolase , Phosphoric Monoester Hydrolases/deficiency , Promoter Regions, Genetic , Proto-Oncogene Proteins/physiology , Proto-Oncogene Proteins c-akt , Transcriptional Activation , Tumor Suppressor Proteins/deficiency
SELECTION OF CITATIONS
SEARCH DETAIL
...