Progesterone Receptor A Stability Is Mediated by Glycogen Synthase Kinase-3β in the Brca1-deficient Mammary Gland

Wang, Shaohui; Liu, Ying; Hsu, Pang-Hung; Lee, Sou-Ying; Kim, Yoon; Lee, Eva Y.-H.P.

doi:10.1074/jbc.m113.476556

Cited by 15 publications

(16 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PR phosphorylation provokes its polyubiquitination, marking the receptor to be degraded by the 26S proteasome (15,18,20,43). Lange et al reported that degradation of PR induced by the progestin R5020 occurs within 4 to 12 hours after treatment in breast cancer cells (15).…”

Section: Discussionmentioning

confidence: 98%

“…It has been reported that four kinases are able to phosphorylate PR. Residue Ser81 can be phosphorylated by casein kinase II (CKII) (17), residues Ser25, Ser190, Ser213, Ser294, Ser554, Ser676 can be phosphorylated by cyclin-dependent kinase 2 (CDK2) (14,16), Ser162 and Ser294 by mitogen activated protein kinases 44 and 42 (MAPK 44/42) (15), and recently, it has been reported that Ser390 is phosphorylated by glycogen synthase kinase-3␤ (GSK3␤) (18). MAPKs are able to phosphorylate PR, increase its transcriptional activity and promote its degradation by the 26S proteasome (20).…”

mentioning

confidence: 99%

See 1 more Smart Citation

PKCα and PKCδ Activation Regulates Transcriptional Activity and Degradation of Progesterone Receptor in Human Astrocytoma Cells

et al. 2015

View full text Add to dashboard Cite

Progesterone regulates cancer cell proliferation and invasion through its receptors (PR-A and PR-B), whose phosphorylation modifies their transcriptional activity and induce their degradation. We identified by in silico analysis a putative residue (Ser400) in PR that might be phosphorylated by protein kinase C (PKC), a family of enzymes involved in the proliferation and infiltration of astrocytomas, the most frequent and aggressive brain tumors. A grade III human astrocytoma-derived cell line was used to study the role of PKC in PR phosphorylation, transcriptional activity, and degradation. Treatment with PKC activator [tetradecanoyl phorbol acetate (TPA)] increased PR phosphorylation in Ser400 after 5 minutes, which in turn induced PR transcriptional activity and its subsequent degradation by the 26S proteasome 3-5 hours after treatment. Silencing or inhibition of PKCα and PKCδ blocked PR phosphorylation and degradation induced by TPA. Both PR isoforms were associated with PKCα and reached the maximum association after 5 minutes of TPA addition. These data correlated with immunnofluorescence assays in which nuclear colocalization of PKCα with PR increased after TPA treatment. We observed a 2-fold increase in cell proliferation after PKC activation with TPA that was reduced with the PR antagonist, RU486. The PR S400A mutant revealed that this residue is essential for PKC-mediated PR phosphorylation and degradation. Our results show a key participation of PKCα and PKCδ in PR regulation and function.

show abstract

Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

PKCα and PKCδ Activation Regulates Transcriptional Activity and Degradation of Progesterone Receptor in Human Astrocytoma Cells

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Other receptors reported to be phosphorylated by GSK3 include the androgen receptor, which reduces its activation of transcription (Salas et al, 2004; Wang et al, 2004), the prolactin receptor, which targets it for proteasomal degradation (Plotnikov et al, 2008), the progesterone receptor, which regulates its stability (Wang et al, 2013b), LRP6, which promotes the recruitment of Axin to LRP6 (Zeng et al, 2005), and the IGF-1 receptor, which regulates its signaling and trafficking (Nemoto et al, 2010; Kelly et al, 2012). …”

Section: Gsk3 Interactions With Receptors and Receptor-coupled Sigmentioning

confidence: 99%

Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases

Beurel

Grieco

Jope

2015

Pharmacology & Therapeutics

1,347

1,178

View full text Add to dashboard Cite

Glycogen synthase kinase-3 (GSK3) may be the busiest kinase in most cells, with over 100 known substrates to deal with. How does GSK3 maintain control to selectively phosphorylate each substrate, and why was it evolutionarily favorable for GSK3 to assume such a large responsibility? GSK3 must be particularly adaptable for incorporating new substrates into its repertoire, and we discuss the distinct properties of GSK3 that may contribute to its capacity to fulfill its roles in multiple signaling pathways. The mechanisms regulating GSK3 (predominantly post-translational modifications, substrate priming, cellular trafficking, protein complexes) have been reviewed previously, so here we focus on newly identified complexities in these mechanisms, how each of these regulatory mechanism contributes to the ability of GSK3 to select which substrates to phosphorylate, and how these mechanisms may have contributed to its adaptability as new substrates evolved. The current understanding of the mechanisms regulating GSK3 is reviewed, as are emerging topics in the actions of GSK3, particularly its interactions with receptors and receptor-coupled signal transduction events, and differential actions and regulation of the two GSK3 isoforms, GSK3α and GSK3β. Another remarkable characteristic of GSK3 is its involvement in many prevalent disorders, including psychiatric and neurological diseases, inflammatory diseases, cancer, and others. We address the feasibility of targeting GSK3 therapeutically, and provide an update of its involvement in the etiology and treatment of several disorders.

show abstract

“…Afterwards cells were washed three times in PBS for 3 min. Cells were then incubated at 37°C overnight (no CO 2 ) with fresh SA-β-gal staining solution at pH 6.0: 1 mg of 5-bromo-4-chloro-3-indolyl β-D galactosidase (X-Gal) per ml (stock solution = 20 mg of potassium ferrocyanide/5 mM potassium ferricyanide/150 mM NaCl/2 mM MgCl2) [32]. Cells were washed twice and observed under an ordinary light microscopy.…”

Section: Methodsmentioning

confidence: 99%

Fuling Granule, a Traditional Chinese Medicine Compound, Suppresses Cell Proliferation and TGFβ-Induced EMT in Ovarian Cancer

et al. 2016

View full text Add to dashboard Cite

The compound fuling granule (CFG) is a traditional Chinese drug which has been used to treat ovarian cancer in China for over twenty years. Nevertheless, the underlying molecular mechanism of its anti-cancer effect remains unclear. In this study, microarray data analysis was performed to search differentially expressed genes in CFG-treated ovarian cancer cells. Several cell cycle and epithelial-mesenchymal transition (EMT) related genes were identified. The microarray analyses also revealed that CFG potentially regulates EMT in ovarian cancer. We also found that, functionally, CFG significantly suppresses ovarian cancer cell proliferation by cell cycle arrest, apoptosis and senescence and the AKT/GSK-3β pathway is possibly involved. Additionally, the invasion and migration ability of ovarian cancer induced by TGFβ is significantly suppressed by CFG. In conclusion, our results demonstrated that CFG suppresses ovarian cancer cell proliferation as well as TGFβ1-induced EMT in vitro. Finally, we discovered that CFG suppresses tumor growth and distant metastasis in vivo. Overall, these findings provide helpful clues to design novel clinical treatments against cancer.

show abstract

Progesterone Receptor A Stability Is Mediated by Glycogen Synthase Kinase-3β in the Brca1-deficient Mammary Gland

Cited by 15 publications

References 31 publications

PKCα and PKCδ Activation Regulates Transcriptional Activity and Degradation of Progesterone Receptor in Human Astrocytoma Cells

PKCα and PKCδ Activation Regulates Transcriptional Activity and Degradation of Progesterone Receptor in Human Astrocytoma Cells

Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases

Fuling Granule, a Traditional Chinese Medicine Compound, Suppresses Cell Proliferation and TGFβ-Induced EMT in Ovarian Cancer

Contact Info

Product

Resources

About