AIM To study the effect of indomethacin (IN) on human colon cancer cell line SW480 with p53 mutant and SW480 transfected wild-type p53 (wtp53/SW480) in vitro and investigate molecular mechanism of anti-tumor effect of IN on colon cancer. METHODS SW480 cells and wtp53/SW480 cells were treated with different concentrations of IN respectively, the expressions of CDK2, CDK4 and p21WAF1/CIP1 prote...

The SCF(FBW7) ubiquitin ligase degrades proteins involved in cell division, growth, and differentiation and is commonly mutated in cancers. The Fbw7 locus encodes three protein isoforms that occupy distinct subcellular localizations, suggesting that each has unique functions. We used gene targeting to create isoform-specific Fbw7-null mutations in human cells and found that the nucleoplasmic Fb...

Selective protein kinase inhibitors were developed on the basis of the unexpected binding mode of 2,6,9-trisubstituted purines to the adenosine triphosphate-binding site of the human cyclin-dependent kinase 2 (CDK2). By iterating chemical library synthesis and biological screening, potent inhibitors of the human CDK2-cyclin A kinase complex and of Saccharomyces cerevisiae Cdc28p were identified...

Chromosomal instability (CIN) is a hallmark of solid tumor biology and is implicated in carcinogenesis. Preferentially eliminating malignant cells by targeting CIN and aneuploidy is an attractive antineoplastic strategy. We previously reported that CDK2 antagonism causes lung cancer cells to undergo anaphase catastrophe and apoptosis through inhibition of phosphorylation of the centrosomal prot...

he decision for a cell to self-replicate requires passage from G1 to S phase of the cell cycle and initiation of another round of DNA replication. This commitment is a critical one that is tightly regulated by many parallel pathways. Significantly, these pathways converge to result in activation of the cyclin-dependent kinase, cdk2. It is, therefore, important to understand all the mechanisms r...

We present evidence that phosphorylation of the C-terminal region of Rb by Cdk4/6 initiates successive intramolecular interactions between the C-terminal region and the central pocket. The initial interaction displaces histone deacetylase from the pocket, blocking active transcriptional repression by Rb. This facilitates a second interaction that leads to phosphorylation of the pocket by Cdk2 a...

Cyclin-dependent kinases (CDKs) are enzymes controlling the eukaryotic cell cycle. CDKs activity is regulated by complex mechanism that includes binding to positive regulatory subunit and phosphorylation at positive and/or negative regulatory sites [1]. CDK2 requires for activation binding to cyclinA or cyclinE. CDK2 obtains full activity by phosphorylation of the Thr160 residue in the activati...

the gene tp53 (also known as protein 53 or tumor protein 53), encoding transcription factor p53, is mutated or deleted in half of human cancers, demonstrating the crucial role of p53 in tumor suppression. there are reports of nearly 250 independent germ line tp53 mutations in over 100 publications. the p53 protein has the structure of a transcription factor and, is made up of several domains. t...

CDK2 is a promising target for the development of anti-cancer agents. It is not an easy task to design CDK2-selective inhibitors which do not exhibit activity for other CDK family members, particularly CDK4, due to a high degree of structural homology among CDK family members. In this study, 4-substituted N-phenylpyrimidin-2-amine derivatives as CDK2 inhibitors were examined to understand the s...

Kinases can switch between active and inactive conformations of the ATP/Mg(2+) binding motif DFG, which has been explored for the development of type I or type II inhibitors. However, factors modulating DFG conformations remain poorly understood. We chose CDK2 as a model system to study the DFG in-out transition on a target that was thought to have an inaccessible DFG-out conformation. We used ...