Modulation of Protein Kinases and Microtubule-associated Proteins and Changes in Ultrastructure in Female Rat Pituitary Cells: Effects of Estrogen and Bromocriptine

Matsuno, Akira; Takekoshi, Susumu; Sanno, Naoko; Utsunomiya, Hirotoshi; Ohsugi, Yoshitaka; Saito, Nozomi; Kanemitsu, H; Tamura, Akira; Nagashima, Tadashi; Ry, Osamura; Watanabe, Keiichi

doi:10.1177/002215549704500605

Cited by 37 publications

(19 citation statements)

References 26 publications

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“…Nevertheless, the existence of ERs in multimeric complexes with growth factor signaling proteins creates the potential for a broader scope of the actions of estrogen and provides support for alternative signal transduction pathways underlying the differentiative effects of estrogen on CNS tissue. Although the traditional view of estrogen action has been that the ligand-activated ER binds directly to EREs, our findings could explain how estrogen and the neurotrophins, via the intermediary of ERK translocation into the nucleus, could regulate the same broad array of ERE-containing genes such as GAP-43 (Costello et al, 1990;Lustig et al, 1991) and tau microtubule-associated protein (Drubin et al, 1985;Matsuno et al, 1997) and non-ERE-containing genes such as ␤-tubulin (Guo and Gorski, 1988) and MAP-2 (Black et al, 1986;Fischer et al, 1991;Lorenzo et al, 1992) involved in neuronal differentiation and neurite growth. …”

Section: Discussionmentioning

confidence: 85%

“…Furthermore, the effect of insulin required the presence of p21Ras, an early signaling component of the mitogenactivated protein (M AP) kinase cascade also used by the neurotrophins. As a result of these observations, taken collectively with the knowledge that estrogen and the neurotrophins can regulate the same cytoskeletal and growth-associated genes [such as M AP-2 (Black et al, 1986;Fischer et al, 1991;Lorenzo et al, 1992), tau microtubule-associated protein (Drubin et al, 1985;Matsuno et al, 1997), ␤-tubulin (Guo and Gorski, 1988), and GAP-43 (Costello et al, 1990;L ustig et al, 1991)], we hypothesized that the M AP kinase cascade also may be used by estrogen in its differentiative actions on the C NS.…”

Section: Abstract: Estradiol; Estrogen Receptor; Erk; Neurotrophins;mentioning

confidence: 92%

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Estrogen-Induced Activation of Mitogen-Activated Protein Kinase in Cerebral Cortical Explants: Convergence of Estrogen and Neurotrophin Signaling Pathways

et al. 1999

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We have shown that estrogen elicits a selective enhancement of the growth and differentiation of axons and dendrites (neurites) in the developing CNS. We subsequently demonstrated widespread colocalization of estrogen and neurotrophin receptors (trk) within developing forebrain neurons and reciprocal transcriptional regulation of these receptors by their ligands. Using organotypic explants of the cerebral cortex, we tested the hypothesis that estrogen/neurotrophin receptor coexpression also may result in convergence or cross-coupling of their signaling pathways. Estradiol elicited rapid (within 5-15 min) tyrosine phosphorylation/activation of the mitogen-activated protein (MAP) kinases, ERK1 and ERK2, that persisted for at least 2 hr. This extracellular signal-regulated protein kinase (ERK) activation was inhibited successfully by the MEK1 inhibitor PD98059, but not by the estrogen receptor (ER) antagonist ICI 182,780, and did not appear to result from estradiol-induced activation of trk. Furthermore, we also found that estradiol elicited an increase in B-Raf kinase activity. The latter and subsequent downstream events leading to ERK activation may be a consequence of our documentation of a multimeric complex consisting of, at least, the ER, hsp90, and B-Raf. These novel findings provide an alternative mechanism for some of the estrogen actions in the developing CNS and could explain not only some of the very rapid effects of estrogen but also the ability of estrogen and neurotrophins to regulate the same broad array of cytoskeletal and growth-associated genes involved in neurite growth and differentiation.

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Section: Discussionmentioning

confidence: 85%

Section: Abstract: Estradiol; Estrogen Receptor; Erk; Neurotrophins;mentioning

confidence: 92%

Estrogen-Induced Activation of Mitogen-Activated Protein Kinase in Cerebral Cortical Explants: Convergence of Estrogen and Neurotrophin Signaling Pathways

et al. 1999

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“…Expression of tau outside the central nervous system, including in epithelial cells, is well documented (21)(22)(23). Tau contains an imperfect estrogen response element upstream of its promoter and is an estrogen-induced protein in cultured neurons and in MCF-7 cells (24)(25)(26). Indeed, three of the four cell lines that expressed tau were ER positive (MCF7, ZR75, and T47D), and we also observed an association between low tau expression and ER-negative status in our clinical specimens.…”

Section: Discussionmentioning

confidence: 99%

Microtubule-associated protein tau: A marker of paclitaxel sensitivity in breast cancer

Rouzier

Rajan

Wagner

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

378

301

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Breast cancers show variable sensitivity to paclitaxel. There is no diagnostic test to identify tumors that are sensitive to this drug. We used U133A chips to identify genes that are associated with pathologic complete response (pCR) to preoperative paclitaxelcontaining chemotherapy in stage I-III breast cancer (n ‫؍‬ 82). Tau was the most differentially expressed gene. Tumors with pCR had significantly lower (P < 0.3 ؋ 10 ؊5 ) mRNA expression. Tissue arrays from 122 independent but similarly treated patients were used for validation by immunohistochemistry. Seventy-four percent of pCR cases were tau protein negative; the odds ratio for pCR was 3.7 (95% confidence interval, 1.6 -8.6; P ϭ 0.0013). In multivariate analysis, nuclear grade (P < 0.01), age <50 (P ϭ 0.03), and taunegative status (P ϭ 0.04) were independent predictors of pCR. Small interfering RNA experiments were performed to examine whether down-regulation of tau increases sensitivity to chemotherapy in vitro. Down-regulation of tau increased sensitivity of breast cancer cells to paclitaxel but not to epirubicin. Tubulin polymerization assay was used to assess whether tau modulates binding of paclitaxel to tubulin. Preincubation of tubulin with tau resulted in decreased paclitaxel binding and reduced paclitaxelinduced microtubule polymerization. These data suggest that low tau expression renders microtubules more vulnerable to paclitaxel and makes breast cancer cells hypersensitive to this drug. Low tau expression may be used as a marker to select patients for paclitaxel therapy. Inhibition of tau function might be exploited as a therapeutic strategy to increase sensitivity to paclitaxel. adjuvant therapy ͉ drug resistance

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“…The association of tumoral MAP-Tau gene transcription with premenopausal patient status, a marker of more aggressive tumor biology, may be a random one in a relatively small sample or may suggest that a subgroup of premenopausal women harbour breast carcinomas of more benign biology. Alternatively, this could be a result of high plasma estrogen levels in premenopausal patients, with increased expression of MAPTau in ER positive tumors of comparatively benign nature, compared to the more aggressive ER negative, potentially BRCA1 or BRCA2-positive, premenopausal breast cancer [30,31]. Interestingly, MAP-Tau is the target of multiple signalling pathways and thereby may represent an important checkpoint for microtubule and cellular functions beyond its interplay with hormonal activities.…”

Section: Discussionmentioning

confidence: 99%

Gene expression of estrogen receptor, progesterone receptor and microtubule-associated protein Tau in high-risk early breast cancer: a quest for molecular predictors of treatment benefit in the context of a Hellenic Cooperative Oncology Group trial

Pentheroudakis

Kalogeras

Wirtz

et al. 2008

Breast Cancer Res Treat

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Background Estrogen receptor (ER) and progesterone receptor (PgR) protein expression carry weak prognostic and moderate predictive utility for the outcome of early breast cancer patients on adjuvant chemohormonotherapy. We sought to study the predictive significance and correlations of transcriptional profiling of the ER, PgR and microtubule-associated protein Tau (MAPTau) genes in early breast cancer. Materials and methods Messenger RNA (mRNA) was extracted from 279 formalinfixed paraffin-embedded breast carcinomas (T1-3N0-1M0) of patients enrolled in the Hellenic Cooperative Oncology Group (HeCOG) trial HE 10/97, evaluating epirubicin-alkylator based adjuvant chemotherapy with or without paclitaxel (E-T-CMF versus E-CMF). Kinetic reverse transcription polymerase chain reaction (kRT-PCR) was applied for assessment of the expression of estrogen receptor, progesterone receptor and MAP-Tau genes in 274 evaluable patients. Cohort-based cut-offs were defined at the 25th percentile mRNA value for ER and PgR and the median for MAP-Tau. Results Two hundred and ten patients (77%) were ER and/or PgR-positive by immunohistochemistry (IHC). Positive ER and MAP-Tau mRNA status was significantly associated with administration of hormonal therapy and low grade, while MAP-Tau mRNA status correlated with premenopausal patient status. MAP-Tau strongly correlated with ER and PgR mRNA status (Spearmann r = 0.52 and 0.64, P\0.001). The observed chance corrected agreement between determination of hormonal receptor status by kRT-PCR and IHC was moderate (Kappa = 0.41) for ER and fair (Kappa = 0.33) for PgR. At a median follow-up of 8 years, univariate analysis adjusted for treatment showed positive ER mRNA status to be of borderline significance for reduced risk of relapse (HR = 0.65, 95% CI 0.41-1.01, P = 0.055) and death (HR = 0.62, 95% CI 0.36-1.05, P = 0.077), while positive MAP-Tau mRNA status was significantly associated with reduced risk of relapse (HR = 0.50, 95% CI 0.32-0.78, P = 0.002) and death (HR = 0.49, 95% CI 0.29-0.83, P = 0.008). In multivariate analysis, only axillary nodal metastases (HR = 2.33, 95% CI 1.05-5.16, P = 0.04) and MAP-Tau mRNA status (HR = 0.46, 95% CI 0.25-0.85, P = 0.01) independently predicted patient outcome. However, MAP-Tau mRNA levels did not predict enhanced benefit from inclusion of paclitaxel in the adjuvant chemotherapy regimen (test for interaction P = 0.99). No correlation was evident between increasing ER and PgR mRNA transcription and increasing benefit from endocrine therapy in 203 ER and/or PgR IHC-positive patients receiving adjuvant hormone therapy (Wald P = 0.54 for ER, 0.51 for PR). Conclusions ER gene transcription carries weak predictive significance for benefit from endocrine therapy or for outcome, with no apparent dose-response association. The predictive significance is possibly exerted via MAP-Tau gene expression, an ER-inducible tubulin modulator with strong predictive significance for patient outcome. However, MAP-Tau mRNA did not predict benefit from the addition...

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Modulation of Protein Kinases and Microtubule-associated Proteins and Changes in Ultrastructure in Female Rat Pituitary Cells: Effects of Estrogen and Bromocriptine

Cited by 37 publications

References 26 publications

Estrogen-Induced Activation of Mitogen-Activated Protein Kinase in Cerebral Cortical Explants: Convergence of Estrogen and Neurotrophin Signaling Pathways

Estrogen-Induced Activation of Mitogen-Activated Protein Kinase in Cerebral Cortical Explants: Convergence of Estrogen and Neurotrophin Signaling Pathways

Microtubule-associated protein tau: A marker of paclitaxel sensitivity in breast cancer

Gene expression of estrogen receptor, progesterone receptor and microtubule-associated protein Tau in high-risk early breast cancer: a quest for molecular predictors of treatment benefit in the context of a Hellenic Cooperative Oncology Group trial

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