Cyclin E is necessary and rate limiting for the passage of mammalian cells through the G1 phase of the cell cycle. Control of cell cycle progression by cyclin E involves cdk2 kinase, which requires cyclin E for catalytic activity. Expression of cyclin E/cdk2 leads to an activation of cyclin A gene expression, as monitored by reporter gene constructs derived from the human cyclin A promoter. Pro...

The cyclin-dependent kinases (CDKs) that promote cell-cycle progression are targets for negative regulation by signals from damaged or unreplicated DNA, but also play active roles in response to DNA lesions. The requirement for activity in the face of DNA damage implies that there are mechanisms to insulate certain CDKs from checkpoint inhibition. It remains difficult, however, to assign precis...

Transforming growth factor beta (TGF-beta)-mediated G(1) arrest previously has been shown to specifically target inactivation of cyclin D:cyclin-dependent kinase (Cdk) 4/6 complexes. We report here that TGF-beta-treated human HepG2 hepatocellular carcinoma cells arrest in G(1), but retain continued cyclin D:Cdk4/6 activity and active, hypophosphorylated retinoblastoma tumor suppressor protein. ...

Inhibitors of histone deacetylase (HDAC) block cell cycle progression at G1 in many cell types. We investigated the mechanism by which trichostatin A (TSA), a specific inhibitor of HDAC, induces G1 arrest in human cervix carcinoma HeLa cells. TSA treatment induced histone hyperacetylation followed by growth arrest in G as well as hypophosphorylation of pRb. The Cdk4 kinase activity was essentia...

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...

Trabeculectomy is the gold standard procedure performed in glaucoma when topical medication and laser intervention failed. In a trabeculectomy, number of clinical trials have shown efficacy ranibizumab minimizing extracellular matrix accumulation at filtering site. Ranibizumab (LucentisTM) drug that targets vascular endothelial growth factor (VEGF). However, to date actual mechanisms this anti-...

The cellular mechanisms regulating intestinal proliferation and differentiation remain largely undefined. Previously, we showed an early induction of the cyclin-dependent kinase (CDK) inhibitor p21Waf1/Cip1 in Caco-2 cells, a human colon cancer line that spontaneously differentiates into a small bowel phenotype. The purpose of our present study was to assess the timing of cell cycle arrest in r...

Speedy (Spy1) is a novel cell cycle regulator that binds and activates cdk2, and was originally identified as a suppressor of Rad1 deficiency in Schizosaccharomyces pombe. Here we demonstrate that overexpression of human Spy1 enhances mammalian cell viability during cellular responses to DNA damage induced by genotoxic agents such as camptothecin, cisplatin, and hydroxyurea. Clonogenic survival...

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...

Adeno-associated virus type 2 (AAV2) seropositivity is negatively correlated with the development of human papillomavirus (HPV)-associated cervical cancer. We have begun analysis of the molecular mechanisms underlying AAV2-mediated onco-suppression through cell cycle regulation in HPV-infected keratinocytes isolated from a low-grade cervical lesion. AAV2 superinfection of HPV type 31b (HPV31b)-...