scholarly journals Autophagy regulates levels of tumor suppressor enzyme protein phosphatase 6

2020 ◽  
Vol 111 (12) ◽  
pp. 4371-4380
Author(s):  
Nobuyuki Fujiwara ◽  
Shusaku Shibutani ◽  
Yusuke Sakai ◽  
Toshio Watanabe ◽  
Issay Kitabayashi ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Protein Phosphatase ◽  
Enzyme Protein

scholarly journals Protein Phosphatase 2A Regulatory Subunit B56α Associates with c-Myc and Negatively Regulates c-Myc Accumulation

2006 ◽  
Vol 26 (7) ◽  
pp. 2832-2844 ◽  
Author(s):  
Hugh K. Arnold ◽  
Rosalie C. Sears
Keyword(s):  
Tumor Suppressor ◽  
Protein Phosphatase ◽  
Cell Function ◽  
Cell Transformation ◽  
Protein Phosphatase 2A ◽  
Regulatory Subunit ◽  
Suppressor Activity ◽  
Tumor Suppressor Activity ◽  
Structural Subunit ◽  
Phosphatase 2A

ABSTRACT Protein phosphatase 2A (PP2A) plays a prominent role in controlling accumulation of the proto-oncoprotein c-Myc. PP2A mediates its effects on c-Myc by dephosphorylating a conserved residue that normally stabilizes c-Myc, and in this way, PP2A enhances c-Myc ubiquitin-mediated degradation. Stringent regulation of c-Myc levels is essential for normal cell function, as c-Myc overexpression can lead to cell transformation. Conversely, PP2A has tumor suppressor activity. Uncovering relevant PP2A holoenzymes for a particular target has been limited by the fact that cellular PP2A represents a large heterogeneous population of trimeric holoenzymes, composed of a conserved catalytic subunit and a structural subunit along with a variable regulatory subunit which directs the holoenzyme to a specific target. We now report the identification of a specific PP2A regulatory subunit, B56α, that selectively associates with the N terminus of c-Myc. B56α directs intact PP2A holoenzymes to c-Myc, resulting in a dramatic reduction in c-Myc levels. Inhibition of PP2A-B56α holoenzymes, using small hairpin RNA to knock down B56α, results in c-Myc overexpression, elevated levels of c-Myc serine 62 phosphorylation, and increased c-Myc function. These results uncover a new protein involved in regulating c-Myc expression and reveal a critical interconnection between a potent oncoprotein, c-Myc, and a well-documented tumor suppressor, PP2A.

Protein phosphatase 2A is essential to maintain active Wnt signaling and its Aβ tumor suppressor subunit is not expressed in colon cancer cells

2014 ◽  
Vol 54 (11) ◽  
pp. 1430-1441 ◽  
Author(s):  
M. Carmen Figueroa-Aldariz ◽  
M. Cristina Castañeda-Patlán ◽  
Paula Santoyo-Ramos ◽  
Alejandro Zentella ◽  
Martha Robles-Flores
Keyword(s):  
Colon Cancer ◽  
Tumor Suppressor ◽  
Wnt Signaling ◽  
Cancer Cells ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Colon Cancer Cells ◽  
Phosphatase 2A

Protein phosphatase SMP1 is a negative regulator of tumor suppressor SMAD2

2006 ◽  
Vol 130 (2) ◽  
pp. 221-222
Author(s):  
X. Lin ◽  
X. Duan ◽  
Y. Liang ◽  
K. Wrighton ◽  
J. Wang ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Protein Phosphatase ◽  
Negative Regulator

scholarly journals Synthetic essentiality of metabolic regulator PDHK1 in PTEN-deficient cells and cancers

2018 ◽  
Author(s):  
Nilanjana Chatterjee ◽  
Evangelos Pazarentzos ◽  
Gorjan Hrustanovic ◽  
Luping Lin ◽  
Erik Verschueren ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Signaling Pathway ◽  
Protein Phosphatase ◽  
Clinical Relevance ◽  
Patient Survival ◽  
Tumor Regression ◽  
Essential Gene ◽  
Aerobic Glycolysis ◽  
Pten Protein

SUMMARYPTEN is a tumor suppressor that is often inactivated in cancer and possesses both lipid and protein phosphatase activities. We report the metabolic regulator PDHK1 (pyruvate dehydrogenase kinase1) is a synthetic-essential gene in PTEN-deficient cancer and normal cells. The predominant mechanism of PDHK1 regulation and dependency is the PTEN protein phosphatase dephosphorylates NFκ;B activating protein (NKAP) and limits NFκB activation to suppress expression of PDHK1, a NFκB target gene. Loss of the PTEN protein phosphatase upregulates PDHK1 to drive aerobic glycolysis and induce PDHK1 cellular dependence. PTEN-deficient human tumors harbor increased PDHK1, which is a biomarker of decreased patient survival, establishing clinical relevance. This study uncovers a PTEN-regulated signaling pathway and reveals PDHK1 as a potential target in PTEN-deficient cancers.SIGNIFICANCEThe tumor suppressor PTEN is widely inactivated in cancers and tumor syndromes. PTEN antagonizes PI3K/AKT signaling via its lipid phosphatase activity. The modest success of PI3K/AKT inhibition in PTEN-deficient cancer patients provides rationale for identifying other vulnerabilities in PTEN-deficient cancers to improve clinical outcomes. We show that PTEN-deficient cells are uniquely sensitive to PDHK1 inhibition. PTEN and PDHK1 co-suppression reduced colony formation and induced cell deathin vitroand tumor regressionin vivo. PDHK1 levels were high in PTEN-deficient patient tumors and associated with inferior patient survival, establishing clinical relevance. Our study identifies a PTEN-regulated signaling pathway linking the PTEN protein phosphatase to the metabolic regulator PDHK1 and provides a mechanistic basis for PDHK1 targeting in PTEN-deficient cancers.

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