Estrogens Down-regulate p27   in Breast Cancer Cells through Skp2 and through Nuclear Export Mediated by the ERK Pathway

Foster, James S.; Fernando, Romaine I.; Ishida, Noriko; Nakayama, Keiichi I.; Wimalasena, Jay

doi:10.1074/jbc.m302830200

Cited by 93 publications

(89 citation statements)

References 82 publications

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“…Recent work indicates that induction of cell growth by E 2 in MCF7 cells may require activity of the PI-3K pathway (Lobenhofer et al, 2000) and the Ras/ERK pathway (Castoria et al, 2001). Furthermore, we reported that G1/S phase transition and Cdk2 activation induced by estrogens is inhibited by dominantnegative (DN) Ras mutants Foster, 2003;Zhu et al, 2003), and the MEK1 inhibitor PD98059 abrogated the increase in cyclin D1 accumulation resulting from estrogen treatment .…”

Section: Inhibition Of Apoptosis In Mcf7mentioning

confidence: 52%

“…The prolonged activation of ERK ( Figure 7A) in contrast to transient activation reported by others (Migliaccio et al, 1996) may be important to maintain the phosphorylation and inactivation of BAD, acting in concert with Akt. Prolonged ERK activation is also required for G1/S transition via enhanced cyclin D1 synthesis (Murphy et al, 2002) and p27 kip1 degradation (Foster, 2003). Together, the data in Figure 5 implicates a critical role for Ras/Raf/ERK in E 2 -promoted MCF7 cell survival.…”

Section: Estradiol Signals Through Two Pathways In Its Antiapoptotic mentioning

confidence: 68%

“…Other investigators have demonstrated that E 2 rapidly activated Ras in MCF7 cells (Keshamouni et al, 2002), and recent work in our laboratory (Foster, 2003) demonstrated that Ras activity is required for nuclear export and degradation of p27 kip1 in response to E 2 . The phosphorylation of BAD at S112 and S136 has been proposed to be mediated by ERK/p90 RSK1 and PI-3K/Akt pathways, respectively, in addition to other mechanisms (Downward, 1999, and references therein).…”

Section: Estradiol-induced Bad Phosphorylation Requires Rasactivated mentioning

confidence: 69%

“…Cells expressing EGFP were considered as coexpressing BAD mutants. We have previously validated the coexpression of plasmid constructs in MCF7 cells (Foster, 2003). Morphological changes in the nuclei were analyzed and condensed/shrunk nuclei were counted as apoptotic as opposed to normal round nuclei (Candolfi et al, 2002).…”

Section: Transient Transfection Microscopic Analysis Of Nuclear Morpmentioning

confidence: 99%

“…In addition to genomic actions, E 2 has been known to exert rapid, likely nongenomic actions both in the whole animal and in cultured cells (Szego, 1974;Huang, 1997;Razandi et al, 2000a,b). Previously, we had observed that estrogens require the function of the Ras, mitogen-activated protein kinase kinase (MEK)1 and extracellular signal-regulated kinase (ERK) pathway to induce G1/S phase transition and elicit down-regulation of the Cdk2 inhibitor p27 kip1 (Foster, 2003;Zhu et al, 2003). Given that E 2 is now known to activate kinase-regulated signal transduction pathways in MCF7 and other cells (Migliaccio et al, 1996, and references therein;…”

Section: Introductionmentioning

confidence: 99%

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Estradiol Abrogates Apoptosis in Breast Cancer Cells through Inactivation of BAD: Ras-dependent Nongenomic Pathways Requiring Signaling through ERK and Akt

Fernando

Wimalasena

2004

MBoC

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113

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Estrogens such as 17-β estradiol (E2) play a critical role in sporadic breast cancer progression and decrease apoptosis in breast cancer cells. Our studies using estrogen receptor-positive MCF7 cells show that E2 abrogates apoptosis possibly through phosphorylation/inactivation of the proapoptotic protein BAD, which was rapidly phosphorylated at S112 and S136. Inhibition of BAD protein expression with specific antisense oligonucleotides reduced the effectiveness of tumor necrosis factor-α, H2O2, and serum starvation in causing apoptosis. Furthermore, the ability of E2 to prevent tumor necrosis factor-α-induced apoptosis was blocked by overexpression of the BAD S112A/S136A mutant but not the wild-type BAD. BAD S112A/S136A, which lacks phosphorylation sites for p90RSK1 and Akt, was not phosphorylated in response to E2 in vitro. E2 treatment rapidly activated phosphatidylinositol 3-kinase (PI-3K)/Akt and p90RSK1 to an extent similar to insulin-like growth factor-1 treatment. In agreement with p90RSK1 activation, E2 also rapidly activated extracellular signal-regulated kinase, and this activity was down-regulated by chemical and biological inhibition of PI-3K suggestive of cross talk between signaling pathways responding to E2. Dominant negative Ras blocked E2-induced BAD phosphorylation and the Raf-activator RasV12T35S induced BAD phosphorylation as well as enhanced E2-induced phosphorylation at S112. Chemical inhibition of PI-3K and mitogen-activated protein kinase kinase 1 inhibited E2-induced BAD phosphorylation at S112 and S136 and expression of dominant negative Ras-induced apoptosis in proliferating cells. Together, these data demonstrate a new nongenomic mechanism by which E2 prevents apoptosis.

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Section: Inhibition Of Apoptosis In Mcf7mentioning

confidence: 52%

Section: Estradiol Signals Through Two Pathways In Its Antiapoptotic mentioning

confidence: 68%

Section: Estradiol-induced Bad Phosphorylation Requires Rasactivated mentioning

confidence: 69%

Section: Transient Transfection Microscopic Analysis Of Nuclear Morpmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Estradiol Abrogates Apoptosis in Breast Cancer Cells through Inactivation of BAD: Ras-dependent Nongenomic Pathways Requiring Signaling through ERK and Akt

Fernando

Wimalasena

2004

MBoC

Self Cite

113

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Acute myelogenous leukemia–derivedSMAD4 mutations target the protein to ubiquitin-proteasome degradation

et al. 2006

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Disruption of transforming growth factor-beta (TGFB1/TGF-beta) signaling contributes to the formation of human hematological malignancies. Smad4, a tumor suppressor, functions as an essential intracellular signal transducer of the TGF-beta signaling pathway. Recent studies have demonstrated that some tumor-derived mutations of Smad4 are associated with protein instability; however, the precise mechanism by which mutated Smad4 proteins undergo rapid degradation remains to be elucidated. A missense mutation of the SMAD4 gene in the Mad homology 1 (MH1) domain (c.305C>T, Pro102Leu) and one frameshift mutation resulting in termination in the Mad homology 2 (MH2) domain (c.1447_1448insAATA, Delta483-552) have been identified in acute myelogenous leukemia. It is not known whether protein instability of these SMAD4 mutants is one of the contributors to TGF-beta signaling disruption in acute myelogenous leukemia. Here we report that these two acute myelogenous leukemia-derived SMAD4 mutants are degraded rapidly when compared to their wild-type counterpart. We have demonstrated that both mutated proteins exhibit enhanced polyubiquitination (or polyubiquitylation) and proteasomal degradation. Importantly, we found that beta-transducin-repeat-containing protein 1 (beta-TrCP1), an F-box protein in the ubiquitin E3 ligase Skp1-Cullin-F-box protein (SCF) complex, directly interacts with and acts as a critical determinant for degradation of both mutated SMAD4 proteins. In addition, small interference RNA (siRNA)-triggered endogenous beta-TrCP1 suppression increased the protein expression level of both overexpressed SMAD4 mutants and endogenous mutated SMAD4 protein in acute myelogenous leukemia cells. These data suggest that mutated SMAD4 proteins undergo rapid degradation in acute myelogenous leukemia cells via SCF(beta-TrCP1) E3 ligase-mediated protein ubiquitination (or ubiquitylation) and subsequent proteasomal degradation.

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Cell cycle control in breast cancer cells

Caldon

Daly

Sutherland

et al. 2005

J of Cellular Biochemistry

198

139

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In breast cancer, cyclins D1 and E and the cyclin-dependent kinase inhibitors p21 (Waf1/Cip1)and p27 (Kip1) are important in cell-cycle control and as potential oncogenes or tumor suppressor genes. They are regulated in breast cancer cells following mitogenic stimuli including activation of receptor tyrosine kinases and steroid hormone receptors, and their deregulation frequently impacts on breast cancer outcome, including response to therapy. The cyclindependent kinase inhibitor p16 (INK4A) also has a critical role in transformation of mammary epithelial cells. In addition to their roles in cell cycle control, some of these molecules, particularly cyclin D1, have actions that are not mediated through regulation of cyclin-dependent kinase activity but may be important for loss of proliferative control during mammary oncogenesis. J. Cell. Biochem. 97: 261-274, 2006. ß 2005 Wiley-Liss, Inc.Key words: cyclin D1; cyclin E; CDK inhibitors; steroid hormones; receptor tyrosine kinasesThe identification of cyclins in the 1980s revolutionized the cell-cycle field and the subsequent functional analysis of cyclins and CDKs provided an unprecedented opportunity to gain a molecular understanding of the cell-cycle machinery, its regulation in normal physiology, and its deregulation during oncogenesis. In the context of breast cancer, cyclins D1 and E were quickly established as early response genes following treatment with known regulators of proliferation including steroids and mitogenic growth factors. Complementary studies showed that these cyclins were deregulated in breast cancer. As the complexity of regulation of CDK activity was revealed, it also became apparent that the cell-cycle machinery was deregulated at multiple levels in breast cancer cells. There is now so much information on the regulation and function of the cell-cycle machinery in breast cancer cells that we have necessarily been selective in the areas covered in this review. We have concentrated here on the cyclins and CDK inhibitors that have been most extensively studied as regulators of the cell cycle in breast cancer cells, as putative mammary oncogenes or tumor suppressor genes, and as potential markers of therapeutic response or outcome: cyclins D1 and E1, and the CDK inhibitors p27 (Kip1), p21 (WAF1/Cip1), and p16 (INK4A). Although this review focuses on cyclins and CDK inhibitors, there are other cell-cycle regulators of known importance in breast cancer, notably the proto-oncogene c-Myc, which has recently been reviewed in this context [Jamerson et al., 2004]. CELL-CYCLE CONTROL MECHANISMSThe cell cycle comprises a series of tightly controlled events that drive the replication of DNA and cell division. It is divided into several phases: preparation for (G 1 phase), and execution of, DNA synthesis (S phase), a second gap phase (G 2 ), and mitosis (M). Quiescence (G 0 ) is a ß 2005 Wiley-Liss, Inc.

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Estrogens Down-regulate p27 in Breast Cancer Cells through Skp2 and through Nuclear Export Mediated by the ERK Pathway

Cited by 93 publications

References 82 publications

Estradiol Abrogates Apoptosis in Breast Cancer Cells through Inactivation of BAD: Ras-dependent Nongenomic Pathways Requiring Signaling through ERK and Akt

Estradiol Abrogates Apoptosis in Breast Cancer Cells through Inactivation of BAD: Ras-dependent Nongenomic Pathways Requiring Signaling through ERK and Akt

Acute myelogenous leukemia–derivedSMAD4 mutations target the protein to ubiquitin-proteasome degradation

Cell cycle control in breast cancer cells

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