G1 Cyclins and Control of the Cell Division Cycle in Normal and Transformed Cells

Hamel, Paul A.; Hanley‐Hyde, Joan

doi:10.3109/07357909709115767

Cited by 34 publications

(22 citation statements)

References 82 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Key targets of these pathways are specific sets of cyclin-cyclin-dependent kinase (CDK) protein complexes that function at specific stages of the cell cycle (34,35). For example, many breast tumors show an aberrant expression and/or amplification of cyclin D1 or cyclin E, (36,37), which both interact with G 1 phase CDKs. In fact, cyclin E expression has been shown to be the best diagnostic marker for breast cancer to date (38).…”

mentioning

confidence: 99%

Indole-3-Carbinol (I3C) Inhibits Cyclin-dependent Kinase-2 Function in Human Breast Cancer Cells by Regulating the Size Distribution, Associated Cyclin E Forms, and Subcellular Localization of the CDK2 Protein Complex

Garcia

Brar

Nguyen

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

Indole-3-carbinol (I3C), a dietary compound found in cruciferous vegetables, induces a robust inhibition of CDK2 specific kinase activity as part of a G 1 cell cycle arrest of human breast cancer cells. Treatment with I3C causes a significant shift in the size distribution of the CDK2 protein complex from an enzymatically active 90 kDa complex to a larger 200 kDa complex with significantly reduced kinase activity. Co-immunoprecipitations revealed an increased association of both a 50 kDa cyclin E and a 75 kDa cyclin E immunoreactive protein with the CDK2 protein complex under I3C-treated conditions, whereas the 90 kDa CDK2 protein complexes detected in proliferating control cells contain the lower molecular mass forms of cyclin E. I3C treatment caused no change in the level of CDK2 inhibitors (p21, p27) or in the inhibitory phosphorylation states of CDK2. The effects of I3C are specific for this indole and not a consequence of the cell cycle arrest because treatment of MCF-7 breast cancer cells with either the I3C dimerization product DIM or the anti-estrogen tamoxifen induced a G 1 cell cycle arrest with no changes in the associated cyclin E or subcellular localization of the CDK2 protein complex. Taken together, our results have uncovered a unique effect of I3C on cell cycle control in which the inhibition of CDK2 kinase activity is accompanied by selective alterations in cyclin E composition, size distribution, and subcellular localization of the CDK2 protein complex.Considerable epidemiological evidence show that diets high in vegetable and fiber lead to low cancer risks and confer protection from various forms of cancers, including breast cancer (1, 2). In particular, consumption of vegetables belonging to the Brassica genus, which includes broccoli, cabbage, and cauliflower, have been reported to correlate with a decrease in mammary tumor incidence (3). These epidemiological studies suggest the existence of naturally occurring compounds in dietary sources that represent a largely untapped source of potential chemotherapeutic molecules. One such phytochemical is indole-3-carbinol (I3C), 1 an autolysis product of gluccosinolates present in Brassica vegetables. Dietary exposure to I3C reduced tumor occurrence and decreased the multiplicity of spontaneous as well as carcinogen-induced mammary tumor formation in rodent model systems (4 -8). Furthermore, diets high in cabbage, a good source of I3C, reduced pulmonary metastasis of mammary tumor implants in mice (9). Consistent with these studies, I3C tested positive as a chemopreventative agent in several short term bioassays relevant to carcinogeninduced DNA damage, tumor initiation and promotion, and oxidative stress (10).When ingested, the low pH environment of the stomach converts a large fraction of I3C into a variety of natural indole oligomers (11-15), such as its diindole products 3,3Ј-diindolylmethane (DIM), and indole[3,2-b]carbazole, which account for many of the in vivo anti-estrogenic and anti-tumorigenic biological activities of I3C (14). In contras...

show abstract

mentioning

confidence: 99%

Indole-3-Carbinol (I3C) Inhibits Cyclin-dependent Kinase-2 Function in Human Breast Cancer Cells by Regulating the Size Distribution, Associated Cyclin E Forms, and Subcellular Localization of the CDK2 Protein Complex

Garcia

Brar

Nguyen

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…phenomenon is likely due to the diverse spectrum of dietary and environmental compounds that can regulate the function and proliferation of mammalian cells by influencing hormone receptor signal transduction pathways (3,4). Several classes of these naturally occurring hormone-like chemicals have been implicated in the control of tumor cell growth and as chemopreventative agents.…”

mentioning

confidence: 99%

“…Regulated changes in the expression and/or activity of cell cycle components that act within G 1 have been closely associated with alterations in the proliferation rate of normal and transformed mammary epithelial cells (4). For example, the estrogen-induced activation of CDK4 and CDK2 during progression of human breast cancer cells between the G 1 and S phases is accompanied by the increased expression of cyclin D1 and decreased association of the CDK inhibitors with the cyclin E-CDK2 complex (36).…”

mentioning

confidence: 99%

Indole-3-carbinol Inhibits the Expression of Cyclin-dependent Kinase-6 and Induces a G1 Cell Cycle Arrest of Human Breast Cancer Cells Independent of Estrogen Receptor Signaling

Cover¹,

Hsieh²,

Tran³

et al. 1998

Journal of Biological Chemistry

246

177

View full text Add to dashboard Cite

Indole-3-carbinol (I3C), a naturally occurring component of Brassica vegetables such as cabbage, broccoli, and Brussels sprouts, has been shown to reduce the incidence of spontaneous and carcinogen-induced mammary tumors. Treatment of cultured human MCF7 breast cancer cells with I3C reversibly suppresses the incorporation of [ 3 H]thymidine without affecting cell viability or estrogen receptor (ER) responsiveness. Flow cytometry of propidium iodide-stained cells revealed that I3C induces a G 1 cell cycle arrest. Concurrent with the I3C-induced growth inhibition, Northern blot and Western blot analyses demonstrated that I3C selectively abolished the expression of cyclin-dependent kinase 6 (CDK6) in a dose-and time-dependent manner. Furthermore, I3C inhibited the endogenous retinoblastoma protein phosphorylation and CDK6 phosphorylation of retinoblastoma in vitro to the same extent. After the MCF7 cells reached their maximal growth arrest, the levels of the p21 and p27 CDK inhibitors increased by 50%. The antiestrogen tamoxifen also suppressed MCF7 cell DNA synthesis but had no effect on CDK6 expression, while a combination of I3C and tamoxifen inhibited MCF7 cell growth more stringently than either agent alone. The I3C-mediated cell cycle arrest and repression of CDK6 production were also observed in estrogen receptor-deficient MDA-MB-231 human breast cancer cells, which demonstrates that this indole can suppress the growth of mammary tumor cells independent of estrogen receptor signaling. Thus, our observations have uncovered a previously undefined antiproliferative pathway for I3C that implicates CDK6 as a target for cell cycle control in human breast cancer cells. Moreover, our results establish for the first time that CDK6 gene expression can be inhibited in response to an extracellular antiproliferative signal.Considerable epidemiological evidence suggests that high vegetable diets correlate with low breast cancer risk (1, 2). This phenomenon is likely due to the diverse spectrum of dietary and environmental compounds that can regulate the function and proliferation of mammalian cells by influencing hormone receptor signal transduction pathways (3, 4). Several classes of these naturally occurring hormone-like chemicals have been implicated in the control of tumor cell growth and as chemopreventative agents. One such substance is the dietary compound indole-3-carbinol (I3C), 1 an autolysis product of a glucosinolate, glucobrassicin, which occurs in Brassica vegetables such as cabbage, broccoli, and Brussels sprouts (5, 6). A recent screen of 90 potential chemopreventative agents in a series of six short term bioassays relevant to carcinogen-induced DNA damage, oxidative stress, and tumor initiation and promotion, revealed I3C to be one of only eight compounds effective in all assays (7). Several studies have shown that exposure to dietary I3C markedly reduces the incidence of spontaneous and carcinogen-induced mammary tumors in rodents (8, 9). For example, I3C administered in the diet or by oral intubation pr...

show abstract

“…The complex cell-cycle machinery mainly consists of cyclins, cyclin dependent kinases and their inhibitors, down-stream targets of the cyclin-dependent kinases which inlcude the Rb family of proteins and their down-stream targets, mainly the E2F family of transcription factors (Adams and Kaelin, 1996a;Cobrinik, 1996;Grana and Reddy, 1995;Kamb, 1995;Sherr, 1994;Sherr and Roberts, 1995;Slansky and Farnham, 1996;Weinberg, 1995). It has been demonstrated that inappropriate activation of any of the positive acting elements or inactivation of the negative acting components can lead to neoplasia (Hamel and Hanley-Hyde, 1997;MacLachlan et al, 1995;Pines, 1995;Sutherland et al, 1995). The components of the cell cycle machinery can respond to the appropriate extra-cellular signals and respond in the proper fashion facilitating proliferation, differentiation or apoptosis (Chellappan, 1994;Kohn, 1998;Lam et al, 1998;Lam and La Thangue, 1994;Wiman, 1993).…”

Section: Introductionmentioning

confidence: 99%

Prohibitin, a potential tumor suppressor, interacts with RB and regulates E2F function

et al. 1999

View full text Add to dashboard Cite

The retinoblastoma tumor suppressor protein and its family members, p107 and p130, are major regulators of the mammalian cell cycle. They exert their growth suppressive eects at least in part by binding the E2F family of transcription factors and inhibiting their transcriptional activity. Agents that disrupt the interaction between Rb family proteins and E2F promote cell proliferation. Here we describe the characterization of a novel interaction between Rb family proteins and a potential tumor suppressor protein, prohibitin. Prohibitin physically interacts with all three Rb family proteins in vitro and in vivo, and was very eective in repressing E2F-mediated transcription. Prohibitin could inhibit the activity of E2Fs 1, 2, 3, 4 and 5, but could not aect the activity of promoters lacking an E2F site. Surprisingly, prohibitin-mediated repression of E2F could not be reversed by adenovirus E1A protein. A prohibitin mutant that could not bind to Rb was impaired in its ability to repress E2F activity and inhibit cell proliferation. We believe that prohibitin is a novel regulator of E2F activity that responds to speci®c signaling cascades.

show abstract

G1 Cyclins and Control of the Cell Division Cycle in Normal and Transformed Cells

Cited by 34 publications

References 82 publications

Indole-3-Carbinol (I3C) Inhibits Cyclin-dependent Kinase-2 Function in Human Breast Cancer Cells by Regulating the Size Distribution, Associated Cyclin E Forms, and Subcellular Localization of the CDK2 Protein Complex

Indole-3-Carbinol (I3C) Inhibits Cyclin-dependent Kinase-2 Function in Human Breast Cancer Cells by Regulating the Size Distribution, Associated Cyclin E Forms, and Subcellular Localization of the CDK2 Protein Complex

Indole-3-carbinol Inhibits the Expression of Cyclin-dependent Kinase-6 and Induces a G1 Cell Cycle Arrest of Human Breast Cancer Cells Independent of Estrogen Receptor Signaling

Prohibitin, a potential tumor suppressor, interacts with RB and regulates E2F function

Contact Info

Product

Resources

About