Differentially regulated expression of activators and inhibitors of cyclin-dependent kinases (cdks) modulate cell cycle progression. In normal fibroblasts, these complexes consist of the cdk inhibitor p21WAF1/PCNA/G1 cyclin/cdk. We now show that bromodeoxyuridine (BrdUrd), a thymidine analogue and radiation sensitizer, inhibits growth and activity of cyclin A-cdk2 kinase in metastatic C8161 and...

In order to elucidate the mechanisms by which estrogens and antiestrogens modulate the growth of breast cancer cells, we have characterized the changes induced by estradiol that occur during the G1 phase of the cell cycle of MCF-7 human mammary carcinoma cells. Addition of estradiol relieves the cell cycle block created by tamoxifen treatment, leading to marked activation of cyclin E-cdk2 compl...

Cyclin E-Cdk2 kinase activation is an essential step in Myc-induced proliferation. It is presumed that this requires sequestration of G(1) cell cycle inhibitors p27(Kip1) and p21(Cip1) (Ckis) via a Myc-induced protein. We provide biochemical and genetic evidence to show that this sequestration is mediated via induction of cyclin D1 and/or cyclin D2 protein synthesis rates. Consistent with this ...

Background: Dysregulation of the CDK/cyclin complex causes aberrant cell cycle entry and progression that can lead to cancer. For instance, CDK2/ cyclin E governs G1-S transition overexpression has been associated with ovarian breast cancers. Our initial studies have demonstrated genetic depletion CDK2 inhibits growth survival in cancer cells overexpressing E. Furthermore, inhibition may be eff...

Recent advances in the understanding of molecular underpinnings metastatic breast cancer have led to identification novel therapeutic targets. The latest update NCCN Guidelines for Breast Cancer reflects a rapidly evolving treatment landscape, highlighting growing importance combination therapies and personalized medicine managing estrogen-receptor (ER)–positive, HER2-positive, triple-negative ...

The widely prevailing view that the cyclin-dependent kinase inhibitors (CKIs) are solely negative regulators of cyclin-dependent kinases (CDKs) is challenged here by observations that normal up-regulation of cyclin D- CDK4 in mitogen-stimulated fibroblasts depends redundantly upon p21(Cip1) and p27(Kip1). Primary mouse embryonic fibroblasts that lack genes encoding both p21 and p27 fail to asse...

Abstract Cyclin-dependent kinase 4/6 (CDK4/6) and PI3K inhibitors synergize in PIK3CA-mutant ER-positive HER2-negative breast cancer models. We conducted a phase Ib trial investigating the safety efficacy of doublet CDK4/6 inhibitor palbociclib plus selective taselisib advanced solid tumors, triplet fulvestrant 25 patients with PIK3CA-mutant, cancer. The therapy response rate was 37.5% [95% con...

Cyclin-dependent kinases (CDKs) regulate the cell division cycle, apoptosis, transcription and differentiation in addition to functions in the nervous system. Deregulation of CDKs in various diseases has stimulated an intensive search for selective pharmacological inhibitors of these kinases. More than 50 inhibitors have been identified, among which >20 have been co-crystallized with CDK2. Thes...

Unrestrained growth is the hallmark of cancer, and disrupted cell-cycle regulation is, therefore, common. CDK4 is the key regulator of the G1–S transition. In complex with cyclin D, CDK4 phosphorylates retinoblastoma protein (Rb) and drives cell-cycle progression, a process inhibited by p16. The p16– CDK4–cyclin D–Rb is aberrant in themajority of cancers and is, thus, a logical target for antic...

BACKGROUND The antihyperglycemic drug metformin may have beneficial effects on the prevention and treatment of cancer. Metformin is known to activate AMP-activated protein kinase (AMPK). It has also been shown to inhibit cyclin D1 expression and proliferation of some cultured cancer cells. However, the mechanisms of action by which metformin mediates cell cycle arrest are not completely underst...