A Surprising Function for the PTEN Tumor Suppressor

Hopkin, Karen

doi:10.1126/science.282.5391.1027

Cited by 37 publications

(17 citation statements)

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“…It has been suggested that PTEN may function, at least in part, through regulation of focal adhesion kinase and the subsequent inhibition of adhesion and migration (47,48). However, several recent reports suggest that PTEN might regulate cell cycle progression by blocking activation of downstream targets of phosphatidylinositol 3-kinase such as the Akt protooncogene (4,27,51). In the mouse, loss of PTEN leads to hyperplasia and dysplasia in the skin, gastrointestinal tract, and prostate and increased tumor formation (10).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Kinase-Associated Phosphatase (KAP) in Breast and Prostate Cancer and Inhibition of the Transformed Phenotype by Antisense KAP Expression

Lee

Reimer

et al. 2000

Molecular and Cellular Biology

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Accumulating evidence suggests that phosphatases play an important role in regulating a variety of signal transduction pathways that have a bearing on cancer. The kinase-associated phosphatase (KAP) is a human dual-specificity protein phosphatase that was identified as a Cdc2-or Cdk2-interacting protein by a yeast two-hybrid screening, yet the biological significance of these interactions remains elusive. We have identified the KAP gene as an overexpressed gene in breast and prostate cancer by using a phosphatase domain-specific differential-display PCR strategy. Here we report that breast and prostate malignancies are associated with high levels of KAP expression. The sublocalization of KAP is variable. In normal cells, KAP is primarily found in the perinuclear region, but in tumor cells, a significant portion of KAP is found in the cytoplasm. Blocking KAP expression by antisense KAP in a tetracycline-regulatable system results in a reduced population of S-phase cells and reduced Cdk2 kinase activity. Furthermore, lowering KAP expression led to inhibition of the transformed phenotype, with reduced anchorage-independent growth and tumorigenic potential in athymic nude mice. These findings suggest that therapeutic intervention might be aimed at repression of KAP gene overexpression in human breast and prostate cancer.Human cancer development is a multistage process that results from the stepwise acquisition of genetic alterations. These alterations may involve the dysregulation of a variety of normal cellular functions, leading to the initiation and progression of a tumor. Among normal cellular functions, regulatory control of the cell cycle plays an important role in normal cell proliferation, and genetic alterations that affect cell cycle control have been shown to be associated with tumor progression (reviewed in references 26, 28, 30, 32, 44, and 46). The transition from one stage of the cell cycle to another is regulated by the transcription of a number of cyclin genes, the degradation of cyclin proteins, and the modification of the cyclin-dependent kinase proteins by phosphorylation (reviewed in references 11, 29, and 30). These controls play important roles in preventing tumorigenesis (26,28,30,31).Cell cycle progression in mammals requires multiple cyclindependent kinases (Cdks) (44). The activity of these kinases depends on their association with a family of positive regulatory protein subunits known as cyclins during the cell cycle. Proteins that interact with Cdks play distinct and specific roles in cell cycle regulation. Among these, the mammalian G 1 Cdk inhibitors have been shown to be involved in diverse processes such as repair of DNA damage, differentiation, tumor suppression, and cellular senescence (12,22,24,25,37,52). The identification of these negative regulators of Cdks has provided key insights into how the cell cycle can be controlled.A Cdk-interacting protein called KAP/Cdi1 was first identified as a novel G 1 -and S-phase dual-specificity phosphatase that associates with Cdk2 and/or Cdc...

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Section: Discussionmentioning

confidence: 99%

Overexpression of Kinase-Associated Phosphatase (KAP) in Breast and Prostate Cancer and Inhibition of the Transformed Phenotype by Antisense KAP Expression

Lee

Reimer

et al. 2000

Molecular and Cellular Biology

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“…It has been proposed that this enzyme suppresses cell proliferation by hydrolyzing PtdIns-3,4,5-P 3 (56). In our unpublished study of this enzyme we find that it has rather broad substrate specificity similar to SopB.…”

Section: Inositol Polyphosphate 4-phosphatasementioning

confidence: 53%

The Role of Phosphatases in Inositol Signaling Reactions

Majerus

1999

Journal of Biological Chemistry

213

233

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“…The demonstration that the human tumor suppressor gene PTEN/MMAC (Hopkin, 1998) which encodes a lipid phosphatase that removes the phosphate from the 3' portion of 3-phosphoinositides (Maehama and Dixon, 1998) highlights the pathophysiological importance of PI3K. Loss of this important tumor suppressor gene product, which modulates PI3K activity, occurs in a variety of human neoplasms (Steck et al, 1997).…”

Section: Roles Of Pi3k-mediated Nf-kb Activation Pathway In Hepatocarmentioning

confidence: 99%

Induction of human MDR1 gene expression by 2-acetylaminofluorene is mediated by effectors of the phosphoinositide 3-kinase pathway that activate NF-κB signaling

et al. 2002

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The expression of P-glycoprotein encoded by the multidrug resistance (MDR1) gene is associated with the emergence of the MDR phenotype in cancer cells. Human MDR1 and its rodent homolog mdr1a and mdr1b are frequently overexpressed in liver cancers. However, the underlying mechanisms are largely unknown. The hepatocarcinogen 2-acetylamino¯uorene (2-AAF) e ciently activates rat mdr1b expression in cultured cells and in Fisher 344 rats. We recently reported that activation of rat mdr1b in cultured cells by 2-AAF involves a cis-activating element containing a NFkB binding site located 7167 to 7158 of the rat mdr1b promoter. 2-AAF activates IkB kinase (IKK), resulting in degradation of IkBb and activation of NF-kB. In this study, we report that 2-AAF could also activate the human MDR1 gene in human hepatoma and embryonic ®broblast 293 cells. Induction of MDR1 by AAF was mediated by DNA sequence located at 76092 which contains a NF-kB binding site. Treating hepatoma cells with 2-AAF activated phosphoinositide 3-kinase (PI3K) and its downstream e ectors Rac1, and NAD(P)H oxidase. Transient transfection assays demonstrated that constitutively activated PI3K and Rac1 enhanced the activation of the MDR1 promoter by 2-AAF. Treatment of hepatoma cells with 2-AAF also activated another PI3K downstream e ector Akt. Transfection of recombinant encoding a dominant activated Akt also enhanced the activation of MDR1 promoter activation by 2-AAF. These results demonstrated that 2-AAF up-regulates MDR1 expression is mediated by the multiple e ectors of the PI3K signaling pathway.

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A Surprising Function for the PTEN Tumor Suppressor

Cited by 37 publications

References 0 publications

Overexpression of Kinase-Associated Phosphatase (KAP) in Breast and Prostate Cancer and Inhibition of the Transformed Phenotype by Antisense KAP Expression

Overexpression of Kinase-Associated Phosphatase (KAP) in Breast and Prostate Cancer and Inhibition of the Transformed Phenotype by Antisense KAP Expression

The Role of Phosphatases in Inositol Signaling Reactions

Induction of human MDR1 gene expression by 2-acetylaminofluorene is mediated by effectors of the phosphoinositide 3-kinase pathway that activate NF-κB signaling

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