The dioxin receptor has tumor suppressor activity in melanoma growth and metastasis

Abstract The Ras–Erk pathway is frequently over-activated in human tumors. Neurofibromatosis type 1 and 2 (NF1, NF2) are characterized by multiple tumors of Schwann cell origin. The NF1 tumor suppressor neurofibromin is a principal Ras-GAP accelerating Ras inactivation, whereas the NF2 tumor suppressor merlin is a scaffold protein coordinating multiple signaling pathways. We have previously reported that merlin interacts with Ras and p120RasGAP. Here, we show that merlin can also interact with the neurofibromin/Spred1 complex via merlin-binding sites present on both proteins. Further, merlin can directly bind to the Ras-binding domain and the kinase domain of Raf1. As the third component of the neurofibromin/Spred1 complex, merlin cannot increase the Ras-GAP activity; rather, it blocks Ras binding to Raf1 by functioning as a ‘selective Ras barrier’. Merlin-deficient Schwann cells require the Ras–Erk pathway activity for proliferation. Accordingly, suppression of the Ras–Erk pathway likely contributes to merlin’s tumor suppressor activity. Taken together, our results, and studies by others, support targeting or co-targeting of this pathway as a therapy for NF2 inactivation-related tumors.

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JunB Breakdown in Mid-/Late G2 Is Required for Down-Regulation of Cyclin A2 Levels and Proper Mitosis

Molecular and Cellular Biology ◽

10.1128/mcb.01620-07 ◽

2008 ◽

Vol 28 (12) ◽

pp. 4173-4187 ◽

Cited By ~ 14

Author(s):

Rosa Farràs ◽

Véronique Baldin ◽

Sandra Gallach ◽

Claire Acquaviva ◽

Guillaume Bossis ◽

...

Keyword(s):

Cell Cycle ◽

Tumor Suppressor ◽

Genetic Instability ◽

S Phase ◽

Subsequent Reduction ◽

Suppressor Activity ◽

Cell Synchronization ◽

Tumor Suppressor Activity ◽

A Cell ◽

Cyclin A2

ABSTRACT JunB, a member of the AP-1 family of dimeric transcription factors, is best known as a cell proliferation inhibitor, a senescence inducer, and a tumor suppressor, although it also has been attributed a cell division-promoting activity. Its effects on the cell cycle have been studied mostly in G1 and S phases, whereas its role in G2 and M phases still is elusive. Using cell synchronization experiments, we show that JunB levels, which are high in S phase, drop during mid- to late G2 phase due to accelerated phosphorylation-dependent degradation by the proteasome. The forced expression of an ectopic JunB protein in late G2 phase indicates that JunB decay is necessary for the subsequent reduction of cyclin A2 levels in prometaphase, the latter event being essential for proper mitosis. Consistently, abnormal JunB expression in late G2 phase entails a variety of mitotic defects. As these aberrations may cause genetic instability, our findings contrast with the acknowledged tumor suppressor activity of JunB and reveal a mechanism by which the deregulation of JunB might contribute to tumorigenesis.

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

Molecular and Cellular Biology ◽

10.1128/mcb.26.7.2832-2844.2006 ◽

2006 ◽

Vol 26 (7) ◽

pp. 2832-2844 ◽

Cited By ~ 150

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.

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