The S phase: Beginning, middle, and end: A perspective

Ford, Heide L.; Pardee, Arthur B.

doi:10.1002/(sici)1097-4644(1998)72:30/31+<1::aid-jcb2>3.0.co;2-e

Cited by 21 publications

(6 citation statements)

References 33 publications

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“…Cyclin A/cdk2 governs S-phase progression and the production of proteins involved in dna synthesis 9,10 . Cyclin A/cdk2 also inactivates E2F [11][12][13][14] .…”

Section: This Scientific Paper Is the Work Of The Author And Was Madementioning

confidence: 78%

Development of Cell-Cycle Inhibitors for Cancer Therapy

Dickson¹,

Schwartz

2009

Current Oncology

193

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Modulation of the cell cycle also contributes to chemotherapy resistance. The cyclin-dependent kinases (cdks), the essential engines of the cell cycle, are therefore rational therapeutic targets. Over the last several years, a new class of anticancer therapy has been developed and extensively tested: inhibitors of cdks.These drugs have been tested as single agents with modest results. However, in combination with traditional cytotoxic chemotherapy, they have the potential to overcome drug resistance and to improve cytotoxic efficacy. THE CELL CYCLE AND ITS REGULATIONThe cell cycle governs the transition from quiescence (G0) to proliferation while ensuring the fidelity of the genetic transcript. The phases associated with dna synthesis (S phase) and mitosis (M phase) are separated by the gaps G1 and G2. The cdks join with regulatory proteins called cyclins to drive the cell through the cycle.Inhibitory proteins [cdk inhibitors (cdkis)] block specific interactions. The Ink4 (inhibitor of cdk4) class of cdkis (p16 Ink4a , p15 Ink4b , p18 Ink4c , and p19 Ink4 ) bind and inhibit cyclin D-associated kinases (cdk2, -4, and -6), and the kinase inhibitor protein (Kip) group of cdkis (p21 Waf1 , p27 Kip1 , and p57 Kip2 ) block the cyclin E/cdk2 and cyclin A/cdk2 complexes 1 .The pattern of cyclin expression defines the cell's progression through the cycle 2,3 . At least 9 cdks (cdk1-cdk9) and many cyclins (cyclin A-cyclin T) are known. The cdk /cyclin complexes are activated by specific phosphorylation of the cdk by cdk7/cyclin H, also called cdk-activating kinase 4 . Specific complexes regulate each step of the cycle. Cyclins D1-D3/cdk2, -4, and -6 drive progression through G1; cyclin E/cdk2 controls entry into S phase; cyclin A/cdk2 controls S-phase progression; cyclin A/ cdk1 (also known as cdc2) controls G2; and cdk1/ cyclin B facilitates mitosis.Entry into the cell cycle (G1) is governed by the restriction point, beyond which progression through the cycle is independent of stimuli such as ABSTRACTThe cell cycle governs the transition from quiescence through cell growth to proliferation. The key parts of the cell cycle machinery are the cyclin-dependent kinases (cdks) and the regulatory proteins called cyclins. The cdks are rational targets for cancer therapy because their expression in cancer cells is often aberrant and their inhibition can induce cell death. Inhibitors of cdks can also block transcription.Several drugs targeting the cell cycle have entered clinical trials. These agents include flavopiridol, indisulam, AZD5438, SNS-032, bryostatin-1, seliciclib, PD 0332991, and SCH 727965. Phase i studies have demonstrated that these drugs can generally be administered safely. Phase ii studies have shown little single-agent activity in solid tumors, but combination studies with cytotoxic chemotherapy have been more promising. In hematologic malignancies, reports have shown encouraging single-agent and combination activity. Pharmacodynamic studies show that the dose and schedule of these drugs are crucial to permit ma...

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“…Cyclin A/cdk2 governs S-phase progression and the production of proteins involved in dna synthesis 9,10 . Cyclin A/cdk2 also inactivates E2F [11][12][13][14] .…”

Section: This Scientific Paper Is the Work Of The Author And Was Madementioning

confidence: 78%

Development of Cell-Cycle Inhibitors for Cancer Therapy

Dickson¹,

Schwartz

2009

Current Oncology

193

View full text Add to dashboard Cite

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“…Relative fold changes of band densities were compared with the control at respective treatment times initiation and progression through S phase as well as the onset of mitosis [34]. In late G2 and early M phase, cyclin A complexes with cdk1 (also known as cdc2) to facilitate entry into the mitotic phase [35]. Cdc2 further drives the cell into M phase through its association with cyclin B [36].…”

Section: Discussionmentioning

confidence: 99%

Novel herbal flavonoids promote apoptosis but differentially induce cell cycle arrest in human colon cancer cell

Auyeung

2009

Invest New Drugs

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Formononetin is a novel herbal isoflavonoid isolated from Astragalus membranaceus, a medicinal plant that possesses antitumorigenic property. We attempted to compare the anticarcinogenic mechanism of formononetin with that of the known proapoptotic flavonoid isoliquiritigenin (ISL) in human cancer cells. We first evaluated the effects of formononetin and ISL on HCT 116 colon cancer cell viability. Immunofluorescence staining was then performed to observe the morphological changes of cancer cells undergoing apoptosis, which had been substantiated using Annexin V-FITC/propidium iodide staining. Western immunoblotting and flow cytometry were also employed to study parameters associated with apoptosis and cell proliferation. Our data show that formononetin and ISL both inhibited the growth of colon cancer cells and promoted apoptosis. These processes were accompanied by caspase activation and downregulation of the antiapoptotic proteins Bcl-2 and Bcl-x(L). Besides, the novel proapoptotic protein NSAID-activated gene (NAG-1) and its upstream regulator were overexpressed in drug-treated cells. Nevertheless, only ISL was found to induce a G2 arrest. These findings exemplify that both formononetin and ISL could cause growth inhibition and facilitate apoptosis in colon cancer cells, while only ISL is capable of inducing phase-specific cell cycle arrest. This suggests that the anticarcinogenic activities of different herbal flavonoids may involve both common and differential mechanisms of action, which could be developed as potential anticancer drugs.

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“…The production of cyclin A and its complex with CDK2 enables S phase progression (Ford and Pardee, 1998). However, orderly S phase progression requires the down-regulation of E2F1 activity, which is partially accomplished by CDK-mediated phosphorylation (Kitagawa et al, 1995;Krek et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

“…CDK-mediated phosphorylation of Rb during G1 phase disrupts the binding of Rb of E2F, allowing E2F to be released and to bind to its heterodimeric partner, DP-1, resulting in the transcription of genes necessary for S phase entry and progression, including cyclin E and cyclin A (Botz et al, 1996;Stiegler et al, 1998). The production of cyclin A and the act of it becoming a complex with CDK2 enable the progression of S phase through the production of other enzymes and proteins involved in DNA synthesis, including histones and proliferating cell nuclear antigen (Ford and Pardee, 1998). However, orderly S phase progression requires the down-regulation of E2F1 activity, which is partially accomplished by CDK-mediated phosphorylation (Kitagawa et al, 1995;Krek et al, 1994).…”

Section: Introductionmentioning

confidence: 99%