Regulation of bcl-2 gene expression in human breast cancer cells by prolactin and its antagonist, hPRL-G129R

Beck, Michael T.; Peirce, Susan K.; Chen, Wen Y.

doi:10.1038/sj.onc.1205637

Cited by 42 publications

(35 citation statements)

References 38 publications

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“…Somewhat unexpectedly, Bcl-2 levels decreased in NB1691 cells as early as 2 hours of thapsigargin treatment and remained lower throughout the time course. Although Bcl-2 has been shown to have a half-life of between 10 and 20 hours depending on the cell type (Beck et al, 2002;Gao and Dou, 2000;Brunelle et al, 2009), there are reports of certain stresses such as glutathione depletion (Celli et al, 1998) or alterations in the level of the pro-apoptotic protein Bim (Jorgensen et al, 2007) significantly decreasing its stability. We also examined MMP-9 expression after ER stress, which is also known to be dependent on eIF4F levels (De Benedetti and Graff, 2004).…”

Section: Resultsmentioning

confidence: 99%

Examination of a second node of translational control in the unfolded protein response

Preston¹,

Hendershot²

2013

Journal of Cell Science

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SummaryThe unfolded protein response (UPR) is a largely cytoprotective signaling cascade that acts to re-establish homeostasis of the endoplasmic reticulum (ER) under conditions of stress by inducing an early and transient block in general protein synthesis and by increasing the folding and degradative capacity of the cell through an extensive transcriptional program. It is well established that the mechanism for the early translational attenuation during ER stress occurs through phosphorylation of eukaryotic initiation factor 2 a (eIF2a) by activated PERK. Our data demonstrate that when eIF2a is dephosphorylated translation is not fully restored to pre-stressed levels. We found that this correlates with reduced mTOR activity and as a result decreases phosphorylation of 4E-BP1, which negatively regulates assembly of the eIF4F complex and cap-dependent translation. The decrease in mTOR activity and 4E-BP1 phosphorylation is associated with activation of AMP kinase, a negative regulator of mTOR, and in the case of some stress conditions, downregulation of signaling through key components of the PI3K pathway. Furthermore, we show that there is a subset of mRNAs that does not recover from UPR-induced translational repression, including those whose translation is particularly sensitive to loss of eIF4F, such as cyclin D1, Bcl-2 and MMP-9. Together these data implicate reduced mTOR activity and 4E-BP1 hypophosphorylation as a second, more restricted mechanism of translational control occurring somewhat later in the UPR.

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Section: Resultsmentioning

confidence: 99%

Examination of a second node of translational control in the unfolded protein response

Preston¹,

Hendershot²

2013

Journal of Cell Science

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“…In MCF7 cells, these pathways lead to altered expression of several cell cycle regulators, including cyclins D1 and B, as well as p21, increasing proliferation (Brockman et al, 2002;Schroeder et al, 2002). However, although PRL has been shown to act as a survival factor in mammary tumor cells in vitro in part via bcl-2 (Beck et al, 2002), we observed increased apoptosis in morphologically normal structures as well as hyperplasias and tumors in the NRL-PRL mice, similar to the responses of murine alveoli and mammary tumors to pituitary isografts (Christov et al, 1993). Both STAT5A and AKT increase alveolar survival during pregnancy and early involution (Humphreys and Hennighausen, 1999;Hu et al, 2001;Schwertfeger et al, 2001;Ackler et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Prolactin induces ERα-positive and ERα-negative mammary cancer in transgenic mice

et al. 2003

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“…So-called G120R-hGH or G129R-hPRL analogs were found to be potent antagonists of their respective receptors in many in vitro bioassays (30,32), including proliferation and PRL receptor-mediated activation of signaling cascades in human breast cancer cell lines in vitro (33)(34)(35). In human mammary tumor cell lines, the PRLR antagonist G129R-hPRL was also reported to induce apoptosis (35,36), to inhibit PRL activation of transcription factor STAT3 (37), and to reduce tumor growth in vivo (38). Despite these encouraging reports arguing for the potential interest of G129R-hPRL as a potent inhibitor of PRL actions in the context of breast cancer, our recent observations clearly show that this PRL analog has its disadvantages, because it fails to antagonize PRL in many situations.…”

mentioning

confidence: 99%

Development of Pure Prolactin Receptor Antagonists

Bernichtein

Kayser

Dillner

et al. 2003

Journal of Biological Chemistry

113

133

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Prolactin (PRL) promotes tumor growth in various experimental models and leads to prostate hyperplasia and mammary neoplasia in PRL transgenic mice. Increasing experimental evidence argues for the involvement of autocrine PRL in this process. PRL receptor antagonists have been developed to counteract these undesired proliferative actions of PRL. However, all forms of PRL receptor antagonists obtained to date exhibit partial agonism, preventing their therapeutic use as full antagonists. In the present study, we describe the development of new human PRL antagonists devoid of agonistic properties and therefore able to act as pure antagonists. This was demonstrated using several in vitro bioassays, including highly sensitive assays able to detect extremely low levels of receptor activation. These new compounds also act as pure antagonists in vivo, as assessed by analyzing their ability to competitively inhibit PRL-triggered signaling cascades in various target tissues (liver, mammary gland, and prostate). Finally, by using transgenic mice expressing PRL specifically in the prostate, which exhibit constitutively activated signaling cascades paralleling hyperplasia, we show that these new PRL analogs are able to completely revert PRL-activated events. These second generation human PRL antagonists are good candidates to be used as inhibitors of growth-promoting actions of PRL.

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Regulation of bcl-2 gene expression in human breast cancer cells by prolactin and its antagonist, hPRL-G129R

Cited by 42 publications

References 38 publications

Examination of a second node of translational control in the unfolded protein response

Examination of a second node of translational control in the unfolded protein response

Prolactin induces ERα-positive and ERα-negative mammary cancer in transgenic mice

Development of Pure Prolactin Receptor Antagonists

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