Insulin/Insulin-like Growth Factor-I and Estrogen Cooperate to Stimulate Cyclin E-Cdk2 Activation and Cell Cycle Progression in MCF-7 Breast Cancer Cells through Differential Regulation of Cyclin E and p21WAF1/Cip1

Lai, Angela; Šarčević, Boris; Prall, Owen W.J.; Sutherland, Robert L.

doi:10.1074/jbc.m100925200

Cited by 84 publications

(63 citation statements)

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“…To our knowledge, interaction of BCL2 family members with c-Jun has not been described before. The nearly simultaneous changes in cyclin D1 mRNA and protein following changes in BAD expression are consistent with changes in cyclin D1 previously described by us and others in MCF7 cells (11)(12)(13)(31)(32)(33).…”

Section: Discussionsupporting

confidence: 74%

Breast Cancer Cell Proliferation Is Inhibited by BAD

Fernando

Foster

Bible

et al. 2007

Journal of Biological Chemistry

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Recent studies on BCL2 family proteins suggest that members of the proapoptotic arm have functions distinct from apoptosis induction. BID has been shown to have a role in the DNA damage response (1), and BAX and BID take part in homologous recombination (2). A prosurvival role for BAD was demonstrated in murine neuronal cells (2), and metabolic functions of BAD were described in mice (3). Growth regulation by BCL2 family proteins has been previously reported, although the mechanisms are poorly defined (4 -6). BAD is devoid of the membrane-anchoring hydrophobic region present in most other BCL2 proteins and it resides primarily in the cytoplasm. Under apoptotic conditions, BAD is found in the mitochondria, binding to BCL2 and BCLxl (7,8 , respectively) and promote its sequestration by 14-3-3 proteins. This mechanism obliterates the inhibitory effects of BAD on prosurvival BCLxl/BCL2 (9).We previously showed in MCF7 breast cancer epithelial cells that estradiol inhibits apoptosis by inducing phosphorylation of BAD (10), and a role for BAD in regulating apoptosis in murine breast epithelial cells has been described in vivo (9). In our studies, we consistently observed that mere overexpression of BAD in MCF7 cells did not cause apoptosis; rather there was an enhanced response once the cells were exposed to an apoptotic stimulus. This suggests levels of regulation between cytoplasmic BAD and its binding and inhibition of BCL2/BCLxL in mitochondria. Similar to our work in MCF7 cells, studies in BAD knock-out mice demonstrated the importance of BAD in survival promotion by growth factors (9). Furthermore, cleavage of long form BAD to a short form was required for its apoptotic role (3). These studies taken together indicate that BAD, by itself, does not necessarily cause apoptosis.In our previous study (10) and in unpublished work, 4 we observed that some portion of BAD localizes in the nucleus and that BAD overexpression led to decreased cell proliferation. In this study, we have studied in detail the cell cycle regulation of MCF7 cells by BAD. This cell line has been utilized as the premier model of hormone-sensitive (estrogen receptor-positive) breast cancer by many laboratories, including our own. In MCF7 cells, cyclin D1 has a rate-limiting role in G 1 -S phase transition (11-13), and both transgenic mouse models and clin-

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Section: Discussionsupporting

confidence: 74%

Breast Cancer Cell Proliferation Is Inhibited by BAD

Fernando

Foster

Bible

et al. 2007

Journal of Biological Chemistry

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“…Additional hormonal changes that might also contribute to reduce breast cancer risk are the reduction in insulin, and increases in IGFBP-1 and -2 (which may reduce IGF-I bioactivity within the breast). Besides estradiol, IGF-I and insulin may exert direct growth-promoting effects on breast epithelium (Kaaks, 1996;Papa & Belfiore, 1996;Chappell et al, 2001;Lai et al, 2001), and there is some evidence that both elevated circulating insulin (Bruning et al, 1992;Del Giudice et al, 1998;Yang et al, 2001) and elevated circulating free IGF-I (Li et al, 2001) may increase breast cancer risk, and worsen breast cancer prognosis (survival time) (Goodwin et al, 2002). An estimation of the breast cancer fraction that might be prevented with the type of diet examined in our study remains difficult, however, as favourable alterations in endogenous hormone levels relatively late in life may not have the same effect on risk as having had a more favourable hormone level lifetime.…”

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confidence: 99%

Effects of dietary intervention on IGF-I and IGF-binding proteins, and related alterations in sex steroid metabolism: the Diet and Androgens (DIANA) Randomised Trial

et al. 2003

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Objective: To assess the effects of a comprehensive change in dietary composition on endogenous hormone metabolism. The specific aim was to examine whether this intervention could lead to favourable changes in insulin sensitivity, levels of IGF-I and IGF-binding proteins (IGFBPs), and total and bioavailable testosterone and estradiol, that would be expected to reduce breast cancer risk. Design: Randomised dietary intervention study; duration of 5 months. Subjects: From a total of 99 postmenopausal women, who had elevated baseline plasma testosterone levels, 49 women were randomly assigned to the dietary intervention arm and the other 50 to a control group. Interventions: Main aspects of the dietary intervention were reductions in the intake of total fat and refined carbohydrates, an increase in the ratio of n-3 over n-6 plus saturated fatty acids, and increased intakes of foods rich in dietary fibre and phytooestrogens. Results: Relative to the control group, women of the intervention group showed a significant reduction of body weight, waist circumference, fasting serum levels of testosterone, C peptide, glucose, and insulin area after glucose tolerance test, and a significant increase of serum levels of sex hormone-binding globulin, IGFBP-1, -2, and growth hormone-binding protein. Serum levels of IGF-I did not change. Conclusion: This comprehensive dietary intervention strategy proved to be successful in inducing changes in endogenous hormone metabolism that might eventually result in reduced breast cancer risk. Additional studies are needed to show whether the dietary intervention and related hormonal changes can be both maintained over longer periods, of at least several years.

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“…The MCF-7 cells were then stimulated to synchronously re-enter the cell cycle by adding 100 nM 17␤-estradiol (E2, Sigma), as described previously (41,50). To monitor cell cycle progression, cells were collected at 15, 21, 27, 33, and 39 h after treatment with 17␤-estradiol, fixed with 70% (v/v) ethanol at 4°C overnight, and stained with 5-bromo-2-deoxyuridine (BrdU) to determine S phase cell population.…”

Section: Methodsmentioning

confidence: 99%

“…MCF-7 cells are dependent on estrogen for growth and, therefore, can be arrested in G 0 /G 1 phase of the cell cycle by the addition of the estrogen receptor antagonist ICI 182780 (ICI). The addition of excess of E2 can then be used to stimulate cells to synchronously reenter the cell cycle (41,50). To quantify the kinetics of G 0 /G 1 -S-phase cell cycle progression by determining the proportion of cells in S phase, cells were labeled with BrdU and analyzed by flow cytometry.…”

Section: Rbp1 Is a Cdk Substrate Which Is Phosphorylated In A Cellmentioning

confidence: 99%

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Cyclin-dependent Kinase-mediated Phosphorylation of RBP1 and pRb Promotes Their Dissociation to Mediate Release of the SAP30·mSin3·HDAC Transcriptional Repressor Complex

Suryadinata

Sadowski

Steel

et al. 2011

Journal of Biological Chemistry

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Eukaryotic cell cycle progression is mediated by phosphorylation of protein substrates by cyclin-dependent kinases (CDKs). A critical substrate of CDKs is the product of the retinoblastoma tumor suppressor gene, pRb, which inhibits G 1 -S phase cell cycle progression by binding and repressing E2F transcription factors. CDK-mediated phosphorylation of pRb alleviates this inhibitory effect to promote G 1 -S phase cell cycle progression. pRb represses transcription by binding to the E2F transactivation domain and recruiting the mSin3⅐histone deacetylase (HDAC) transcriptional repressor complex via the retinoblastoma-binding protein 1 (RBP1). RBP1 binds to the pocket region of pRb via an LXCXE motif and to the SAP30 subunit of the mSin3⅐HDAC complex and, thus, acts as a bridging protein in this multisubunit complex. In the present study we identified RBP1 as a novel CDK substrate. RBP1 is phosphorylated by CDK2 on serines 864 and 1007, which are N-and C-terminal to the LXCXE motif, respectively. CDK2-mediated phosphorylation of RBP1 or pRb destabilizes their interaction in vitro, with concurrent phosphorylation of both proteins leading to their dissociation. Consistent with these findings, RBP1 phosphorylation is increased during progression from G 1 into S-phase, with a concurrent decrease in its association with pRb in MCF-7 breast cancer cells. These studies provide new mechanistic insights into CDK-mediated regulation of the pRb tumor suppressor during cell cycle progression, demonstrating that CDK-mediated phosphorylation of both RBP1 and pRb induces their dissociation to mediate release of the mSin3⅐HDAC transcriptional repressor complex from pRb to alleviate transcriptional repression of E2F.The eukaryotic cell cycle is an evolutionarily conserved process that regulates cell division from unicellular organisms such as yeast through to humans. In response to developmental cues, appropriate growth conditions, and stimulation by mitogenic growth factors, cell division is promoted by activation of the key enzymes responsible for promoting cell cycle progression, the cyclin-dependent kinases (CDKs).4 These dimeric enzymes consist of a cyclin regulatory subunit, which binds and activates a CDK protein kinase subunit (1). In mammalian cells, progression through the different cell cycle phases is mediated by different CDKs. Therefore, cyclin D/CDK4/6 controls progression through G 1 phase (2, 3) followed by cyclin E/CDK2 kinase activity promoting G 1 -S phase progression (4). Cyclin A/CDK2 is important during S phase and cyclin A/CDK1 activity peaks during G 2 phase (5). Finally, cyclin B/CDK1 activity is required for mitosis (6, 7). CDKs mediate cell cycle progression through phosphorylation of protein substrates to alter their biological function(s). Different CDKs phosphorylate distinct substrates to promote progression through different cell cycle phases due to their differential temporal activities, substrate specificities, and subcellular localization, although some substrates are phosphorylated by different CD...

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Insulin/Insulin-like Growth Factor-I and Estrogen Cooperate to Stimulate Cyclin E-Cdk2 Activation and Cell Cycle Progression in MCF-7 Breast Cancer Cells through Differential Regulation of Cyclin E and p21WAF1/Cip1

Cited by 84 publications

References 48 publications

Breast Cancer Cell Proliferation Is Inhibited by BAD

Breast Cancer Cell Proliferation Is Inhibited by BAD

Effects of dietary intervention on IGF-I and IGF-binding proteins, and related alterations in sex steroid metabolism: the Diet and Androgens (DIANA) Randomised Trial

Cyclin-dependent Kinase-mediated Phosphorylation of RBP1 and pRb Promotes Their Dissociation to Mediate Release of the SAP30·mSin3·HDAC Transcriptional Repressor Complex

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