OCT4 Represses Inflammation and Cell Injury During Orchitis by Regulating CIP2A Expression

Octamer-binding transcription factor 4 (OCT4) and cancerous inhibitor of protein phosphatase 2A (CIP2A) are upregulated in testicular cancer and cell lines. However, its contribution to orchitis (testicular inflammation) is unclear and was thus, investigated herein. Cell-based experiments on a lipopolysaccharide (LPS)-induced orchitis mouse model revealed robust inflammation, apoptotic cell death, and redox disorder in the Leydig (interstitial), Sertoli (supporting), and, germ cells. Meanwhile, real-time quantitative PCR revealed low OCT4 and CIP2A levels in testicular tissue and LPS-stimulated cells. A gain-of-function study showed that OCT4 overexpression not only increased CIP2A expression but also repressed LPS-induced inflammation, apoptosis, and redox disorder in the aforementioned cells. Furthermore, the re-inhibition of CIP2A expression by TD-19 in OCT4-overexpressing cells counteracted the effects of OCT4 overexpression on inflammation, apoptosis, and redox equilibrium. In addition, our results indicated that the Keap1-Nrf2-HO-1 signaling pathway was mediated by OCT4 and CIP2A. These findings provide insights into the potential mechanism underlying OCT4- and CIP2A-mediated testicular inflammation.

Download Full-text

Protein Phosphatase 2A Inactivates Bcl2’s Antiapoptotic Function by Dephosphorylation and Up-Regulation of Bcl2-p53 Binding.

Blood ◽

10.1182/blood.v108.11.1436.1436 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1436-1436

Author(s):

Xingming Deng ◽

Fengqin Gao ◽

Tammy Flagg ◽

W. Stratford May

Keyword(s):

Cell Death ◽

Cell Survival ◽

Okadaic Acid ◽

Protein Phosphatase ◽

Apoptotic Cell ◽

Protein Phosphatase 2A ◽

Survival Function ◽

Phosphorylation Site ◽

Apoptotic Cell Death ◽

Phosphatase 2A

Abstract DNA damage-induced p53/Bcl2 interaction at the outer mitochondrial membranes results in a Bcl2 conformational change and loss of its antiapoptotic function. Our data now indicate that either treatment of cells with the protein phosphatase 2A (PP2A) inhibitor, okadaic acid (10 nM), or specific disruption of PP2A activity by the expression of SV40 small tumor antigen enhances Bcl2 phosphorylation and suppresses the cisplatin-stimulated Bcl2-p53 interaction in association with prolonged cell survival. By contrast, C2-ceramide, a potent PP2A activator, reduces Bcl2 phosphorylation and increases Bcl2-p53 binding and promotes apoptotic cell death, suggesting that PP2A may function as a physiological regulator of Bcl2 by, at least in part, affecting its association with p53. Overexpression of the PP2A catalytic subunit (PP2A/C) suppresses Bcl2 phosphorylation in association with increased p53-Bcl2 binding and apoptotic cell death. By contrast, specific depletion of PP2A/C by RNA interference enhances Bcl2 phosphorylation, suppresses p53-Bcl2 interaction and prolongs cell survival. Purified PP2A can directly enhance the formation of the p53-Bcl2 complex in vitro in an okadaic acid-sensitive manner, supporting a direct mechanism. Importantly, PP2A directly interacts with Bcl2 at its BH4 domain which may function as the PP2A ‘docking site’ to potentially ‘bridge’ PP2A to the flexible loop domain which contains the physiological serine 70 phosphorylation site. Thus, PP2A may provide a double whammy to Bcl2’s survival function by both dephosphorylating and enhancing p53-Bcl2 binding. Therapeutically stimulating Bcl2 dephosphorylation and/or increasing Bcl2/p53 binding by activating PP2A may represent an efficient and novel antineoplastic approach.

Download Full-text

Protein phosphatase 2A inactivates Bcl2's antiapoptotic function by dephosphorylation and up-regulation of Bcl2-p53 binding

Blood ◽

10.1182/blood-2008-06-165134 ◽

2009 ◽

Vol 113 (2) ◽

pp. 422-428 ◽

Cited By ~ 62

Author(s):

Xingming Deng ◽

Fengqin Gao ◽

W. Stratford May

Keyword(s):

Conformational Change ◽

Protein Phosphatase ◽

Apoptotic Cell ◽

Protein Phosphatase 2A ◽

Survival Function ◽

Phosphorylation Site ◽

Hematologic Malignancies ◽

T Antigen ◽

Phosphatase 2A

Abstract Bcl2 is associated with chemoresistance and poor prognosis in patients with various hematologic malignancies. DNA damage-induced p53/Bcl2 interaction at the outer mitochondrial membrane results in a Bcl2 conformational change with loss of its antiapoptotic activity in interleukin-3–dependent myeloid H7 cells. Here we find that specific disruption of protein phosphatase 2A (PP2A) activity by either expression of small t antigen or depletion of PP2A/C by RNA interference enhances Bcl2 phosphorylation and suppresses cisplatin-stimulated p53/Bcl2 binding in association with prolonged cell survival. By contrast, treatment of cells with C2-ceramide (a potent PP2A activator) or expression of the PP2A catalytic subunit (PP2A/C) inhibits Bcl2 phosphorylation, leading to increased p53/Bcl2 binding and apoptotic cell death. Mechanistically, PP2A-mediated dephosphorylation of Bcl2 in vitro promotes its direct interaction with p53 as well as a conformational change in Bcl2. PP2A directly interacts with the BH4 domain of Bcl2 as a docking site to potentially “bridge” PP2A to Bcl2's flexible loop domain containing the target serine 70 phosphorylation site. Thus, PP2A may provide a dual inhibitory effect on Bcl2's survival function by both dephosphorylating Bcl2 and enhancing p53-Bcl2 binding. Activating PP2A to dephosphorylate Bcl2 and/or increase Bcl2/p53 binding may represent an efficient and novel approach for treatment of hematologic malignancies.

Download Full-text

Senkyunolide A protects corticosterone-induced cell apoptosis via modulating protein phosphatase 2A and α-synuclein

10.1101/145326 ◽

2017 ◽

Author(s):

Shenglan Gong ◽

Jin Zhang ◽

Zhouke Guo ◽

Wenjun Fu

Keyword(s):

Pc12 Cells ◽

Protein Phosphatase ◽

Cell Apoptosis ◽

Neurological Disorders ◽

Cell Injury ◽

Cell Model ◽

Neuroprotective Effects ◽

Phosphatase 2A ◽

Underlying Mechanisms ◽

Pp2a Inhibitor

AbstractDan-zhi-xiao-yao-san is a Traditional Chinese Medicine (TCM) formula that is widely used to treat depression related neurological disorders, however, the active compound(s) and underlying mechanisms are unclear. In the present study, we found that senkyunolide A (SenA) has neuroprotective effects in corticosterone (Cort)-induced depression cell model in PC12 cells. Firstly, we found that SenA protects Cort-induced cell injury in PC12 cells. In addition, SenA attenuates Cort-induced the reduction of phosphatase 2A (PP2A) activities, and the increase of p-PP2A, α-syn and p-α-syn-Ser129 levels. Furthermore, PP2A inhibitor okadaic acid (OA) decreased, and PP2A activator D-erythro-Sphingosine (SPH) increased Cort-induced cell apoptosis. Importantly, we also found that the neuroprotective effects of SenA in Cort-induced cell injury via modulating α-syn levels. Collectively, our results suggest that the neuroprotective effects of SenA in Cort-induced depression cell model via modulating PP2A activities and α-syn levels, and bring a breakthrough to the anti-depression mechanisms for natural compound SenA.

Download Full-text