Protein phosphatase 2A regulates life and death decisions via Akt in a context-dependent manner

Andrabi, Shaida; Gjoerup, Ole; Kean, Jennifer A.; Roberts, Thomas M.; Schaffhausen, Brian

doi:10.1073/pnas.0706696104

Cited by 92 publications

(116 citation statements)

References 33 publications

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“…PyST did not affect GSK3 phosphorylation. This pattern of differential effects has been noted previously in cell death experiments (17). Unlike PyST, SVST had a general enhancing effect on the same substrates.…”

Section: Action Of Both Svst and Pyst In Differentiation Issupporting

confidence: 48%

“…Polyomavirus small T antigens (STs) bind to the PP2A A and C subunits, displacing or preventing B subunits from binding (15,16). Murine polyoma ST antigen (PyST) causes apoptosis (17) or inhibits differentiation through association with PP2A (18). Although simian virus SV40 ST antigen (SVST) also binds PP2A, it does not do either of these things.…”

mentioning

confidence: 99%

“…SVST signaling through Akt contributes to transformation (21). Depending on cell conditions, PyST can kill or protect 3T3 cells in a PP2A/Akt-dependent manner (17).…”

mentioning

confidence: 99%

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Protein Phosphatase 2A Isoforms Utilizing Aβ Scaffolds Regulate Differentiation through Control of Akt Protein

Hwang

Jiang

Kulkarni

et al. 2013

Journal of Biological Chemistry

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Background: Protein phosphatase 2A (PP2A) controls most cell signaling, but the current understanding of its many isoforms, e.g. as tumor suppressors, is limited. Results: Differentiation was controlled by the small fraction of PP2A using the A␤ scaffold. Conclusion: PP2A A␤ regulates Akt. Significance: Given the extreme importance of Akt in cancer, these findings help explain why A␤ is a tumor suppressor.

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Section: Action Of Both Svst and Pyst In Differentiation Issupporting

confidence: 48%

mentioning

confidence: 99%

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Protein Phosphatase 2A Isoforms Utilizing Aβ Scaffolds Regulate Differentiation through Control of Akt Protein

Hwang

Jiang

Kulkarni

et al. 2013

Journal of Biological Chemistry

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“…Akt-1 activation, however, may be anti-or proapoptotic depending on the context of cell signaling (27). In the case of LB-1.2 inhibition of PP2A, an increase in pAkt-1 activates Plk-1, a regulator of a mitotic checkpoint and of the activity of TCTP.…”

Section: Resultsmentioning

confidence: 99%

“…6). In the face of chemotherapy-induced DNA damage and disordered cell replication, LB-1.2 up-regulates Akt-1, which has the potential to stimulate cell growth, and, at the same time, interferes with p53-mediated cell cycle arrest by stabilizing MDM2 (27). An increase in pAkt-1 activates Plk-1, interfering with activation of a checkpoint at G2/M (5,8) and activating TCTP by phosphorylation (21).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of serine/threonine phosphatase PP2A enhances cancer chemotherapy by blocking DNA damage induced defense mechanisms

Lü

Kovach

Johnson

et al. 2009

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

142

168

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A variety of mechanisms maintain the integrity of the genome in the face of cell stress. Cancer cell response to chemotherapeutic and radiation-induced DNA damage is mediated by multiple defense mechanisms including polo-like kinase 1 (Plk-1), protein kinase B (Akt-1), and/or p53 pathways leading to either apoptosis or cell cycle arrest. Subsequently, a subpopulation of arrested viable cancer cells may remain and recur despite aggressive and repetitive therapy. Here, we show that modulation (activation of Akt-1 and Plk-1 and repression of p53) of these pathways simultaneously results in paradoxical enhancement of the effectiveness of cytotoxic chemotherapy. We demonstrate that a small molecule inhibitor, LB-1.2, of protein phosphatase 2A (PP2A) activates Plk-1 and Akt-1 and decreases p53 abundance in tumor cells. Combined with temozolomide (TMZ; a DNA-methylating chemotherapeutic drug), LB-1.2 causes complete regression of glioblastoma multiforme (GBM) xenografts without recurrence in 50% of animals (up to 28 weeks) and complete inhibition of growth of neuroblastoma (NB) xenografts. Treatment with either drug alone results in only short-term inhibition/regression with all xenografts resuming rapid growth. Combined with another widely used anticancer drug, Doxorubicin (DOX, a DNA intercalating agent), LB-1.2 also causes marked GBM xenograft regression, whereas DOX alone only slows growth. Inhibition of PP2A by LB-1.2 blocks cell-cycle arrest and increases progression of cell cycle in the presence of TMZ or DOX. Pharmacologic inhibition of PP2A may be a general method for enhancing the effectiveness of cancer treatments that damage DNA or disrupt components of cell replication.

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Cellular localization of CIP2A determines its prognostic impact in superficial spreading and nodular melanoma

et al. 2015

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Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an important oncogene contributing to cancer progression partially by regulating cMYC and AKT. We examined CIP2A expression in cutaneous melanomas, its association with clinicopathological parameters and mapped molecular mechanisms regulated by CIP2A in vitro. CIP2A expression was analyzed by immunohistochemistry in 17 nevi, 132 primary melanomas and 49 metastases. Effects of siRNA-mediated down-regulation on proliferation, apoptosis and signaling pathways were assessed in melanoma cell lines. In superficial spreading melanomas (SSM), high nuclear CIP2A expression was associated with poor overall survival (OS) (P = 0.0018). Surprisingly, high cytoplasmic expression was related to improved relapse-free (P = 0.031) and OS (P = 0.014) in nodular melanomas (NM). In vitro experiments revealed that CIP2A can regulate proliferation and/or apoptosis partially through the PI3K/AKT pathway but also independently. In summary, CIP2A could represent a potential therapeutic target in SSM. However, in NM cytoplasmic CIP2A is associated with improved prognosis indicating that CIP2A has distinct, complex functions dependent on the molecular context and histological subtype. As seen in other cancer types, CIP2A can influence cMYC and AKT, but our data also suggest that in melanoma it has additional targets which need to be identified.

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Protein phosphatase 2A regulates life and death decisions via Akt in a context-dependent manner

Cited by 92 publications

References 33 publications

Protein Phosphatase 2A Isoforms Utilizing Aβ Scaffolds Regulate Differentiation through Control of Akt Protein

Protein Phosphatase 2A Isoforms Utilizing Aβ Scaffolds Regulate Differentiation through Control of Akt Protein

Inhibition of serine/threonine phosphatase PP2A enhances cancer chemotherapy by blocking DNA damage induced defense mechanisms

Cellular localization of CIP2A determines its prognostic impact in superficial spreading and nodular melanoma

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