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...

In eukaryotes, cell cycle progression is controlled by cyclin/cyclin-dependent kinase (CDK) pairs. To better understand the details of this process, it is necessary to dissect the CDK's substrate pool in a cyclin- and cell cycle stage-specific way. Here, we report a mass spectrometry-based method that couples rapid isolation of native kinase-substrate complexes to on-bead phosphorylation with h...

Cyclin-dependent kinase 4 (CDK4)/cyclin D complexes are expressed early in the G(1) phase of the cell cycle and stimulate the expression of genes required for G(1) progression by phosphorylation of the product of the retinoblastoma gene, pRb. To elaborate the molecular pathway of CDK4 activation and substrate selection we have determined the structure of nonphosphorylated CDK4/cyclin D3. This s...

The cyclin-dependent kinase (CDK) inhibitor p21WAFI/CIP1is a multidoniain. multifunctional protein and a candidate tumor suppressor. Here, we show that, among rationally designed and tumor-associated mutants of hu man p21 ectopically expressed in U-2-OS cells, those that are selectively deficient in binding to either cyclin or CDK are partially impaired in inhib iting endogenous CDK activities ...

The cyclin-dependent kinase (CDK) inhibitor p21WAFI/CIP1is a multidoniain. multifunctional protein and a candidate tumor suppressor. Here, we show that, among rationally designed and tumor-associated mutants of hu man p21 ectopically expressed in U-2-OS cells, those that are selectively deficient in binding to either cyclin or CDK are partially impaired in inhib iting endogenous CDK activities ...

more recently medical chemistry research has been focused on proteins that drive and controlcell cycle progression. among them, the cyclin dependent kinases (cdk’s) are a group ofserine/threonine kinases, which rule the transition between successive stages of the cell cycle. theactivity of cdk’s is regulated by multiple mechanisms, including binding to cyclins, which is a broadclass of positive...

In normal fibroblasts CDKs exist predominantly in p21/PCNA/cycl in/CDK quaternary complexes, whereas in p53-deficient cells, p21 expression is depressed and the kinases are reduced to a cyclin/CDK binary state, p21 is a universal cyclin kinase inhibitor, but we show here that p21-containing complexes exist in both catalytically active and inactive forms. This finding challenges the current view...

We have used a chemically diverse panel of kinase inhibitors to assess the chemical similarity of the ATP-binding sites of cyclin-dependent kinase (CDK) subfamily members in a range of activation states. Using this approach, we find that different activation states of a particular CDK may differ from each other as much as different CDKs in the same activation state. We also find that inhibitors...

Several mammalian forkhead transcription factors have been shown to impact on cell cycle regulation and are themselves linked to cell cycle control systems. Here we have investigated the little studied mammalian forkhead transcription factor FOXK2 and demonstrate that it is subject to control by cell cycle-regulated protein kinases. FOXK2 exhibits a periodic rise in its phosphorylation levels d...