Merlin Neutralizes the Inhibitory Effect of Mdm2 on p53

Kim, Hongtae; Kwak, Noh-Jin; Lee, Joo Yong; Choi, Byung Hyune; Lim, Yejee; Ko, Young Jin; Kim, Young-Hoon; Huh, Pil Woo; Lee, Kweon-Haeng; Rha, Hyoung Kyun; Wang, Young-Pil

doi:10.1074/jbc.m305526200

Cited by 58 publications

(49 citation statements)

References 38 publications

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“…In addition, recent studies have suggested a role for NF2 in the inhibition of the p53 regulatory protein, Mdm2, whereby NF2 promotes degradation of Mdm2, thus stabilizing p53. Such findings parallel those described in our mouse model and suggest potential functional consequences for NF2 interaction with Tantigen and/or p53 (Kim et al, 2004). One may envision a scenario in which T-antigen may bind to p53 and/or NF2, thus inactivating the G1/S checkpoint and possibly other cell cycle regulatory pathways downstream of NF2.…”

Section: Discussionsupporting

confidence: 62%

JCV T-antigen interacts with the neurofibromatosis type 2 gene product in a transgenic mouse model of malignant peripheral nerve sheath tumors

et al. 2004

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Section: Discussionsupporting

confidence: 62%

JCV T-antigen interacts with the neurofibromatosis type 2 gene product in a transgenic mouse model of malignant peripheral nerve sheath tumors

et al. 2004

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“…Moreover, we recently observed that merlin increased p53 activity by inducing MDM2 degradation in NIH3T3 cells (35). Considering all of these results and related papers, it would appear that merlin has multiple activities for tumor suppression, one of which might be the suppression of TRBP function reported herein.…”

Section: Discussionmentioning

confidence: 92%

Merlin, a Tumor Suppressor, Interacts with Transactivation-responsive RNA-binding Protein and Inhibits Its Oncogenic Activity

Lee¹,

Kim²,

Ryu³

et al. 2004

Journal of Biological Chemistry

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The neurofibromatosis type 2 gene-encoded protein, merlin, is related to the ERM (ezrin, radixin, and moesin) family of membrane-cytoskeleton-associated proteins. Recent studies suggest that the loss of neurofibromatosis type 2 function contributes to tumor development and metastasis. Although the cellular functions of merlin as a tumor suppressor are relatively well characterized, the cellular mechanism whereby merlin controls cell proliferation from membrane locations is still poorly understood. During our efforts to find potential merlin modulators through protein-protein interactions, we identified transactivation-responsive RNAbinding protein (TRBP) as a merlin-binding protein in a yeast two-hybrid screen. The interaction between TRBP and merlin was confirmed by glutathione S-transferase pull-down assays, co-immunoprecipitation, and co-localization experiments. The carboxyl-terminal regions of each protein were responsible for their interaction. Cells overexpressing TRBP showed enhanced cell growth in cell proliferation assays and also exhibited transformed phenotypes, such as anchorage-independent cell growth and tumor development in mouse xenografts. Merlin efficiently inhibited these oncogenic activities of TRBP in our experiments. These results provide the first clue to the functional interaction between TRBP and merlin and suggest a novel mechanism for the tumor suppressor function of merlin both in vitro and in vivo.

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“…Interestingly, promyelocytic leukemia regulates p53 stability by sequestering MDM2 to the nucleolus (57). Similarly, merlin (neurofibromatosis 2) increases the p53 stability by inhibiting the MDM2-mediated degradation of p53 (58). PTEN physically associates with endogenous p53 and regulates the transcriptional activity of p53 by modulating its DNA binding (59).…”

Section: Discussionmentioning

confidence: 99%

WOX1 Is Essential for Tumor Necrosis Factor-, UV Light-, Staurosporine-, and p53-mediated Cell Death, and Its Tyrosine 33-phosphorylated Form Binds and Stabilizes Serine 46-phosphorylated p53

Chang

Doherty

Ensign

et al. 2005

Journal of Biological Chemistry

117

270

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Hyaluronidases and hyaluronan are important mediators of tissue remodeling and cancer cell metastasis. Metastatic and malignant breast and prostate cancers frequently overexpress hyaluronidases and hyaluronan (1, 2). Hyaluronidases PH-20, Hyal-1, and Hyal-2 are known to induce the expression of a candidate tumor suppressor WW domaincontaining oxidoreductase WOX1 (also known as WWOX, FOR, or WWOXv1) (3-5).The human WWOX gene, which comprises nine exons encoding the WWOX/WOX1 family proteins, is located on a fragile site on the chromosome ch16q23.3-24.1 (6 -9). Eight mRNA transcripts of the WWOX gene have been found so far (7). However, it is still not known whether all of the mRNA transcripts are translated successfully into proteins. Isoforms WWOXv1 (46 kDa), WWOXv2 (42 kDa), and WWOXv8 (60 kDa) and several other small proteins can be found in normal and several types of cancer cells (3, 8 -11). 3 Genetic alterations of the WWOX gene and disappearance of WWOX/WOX1 family proteins have been shown in multiple types of cancers, especially at an invasive or a metastatic stage (8,9,(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Hypermethylation of the WWOX gene may inactivate its expression (21). In contrast, significant up-regulation of WWOX/WOX1 family proteins has been shown during progression of breast, prostate and other cancers to a premetastatic state (10,22,23). Also, absent expression of these family proteins in metastatic cancer cells is not necessarily due to disruption of the WWOX gene. We have recently determined that post-transcriptional blockade of the fulllength mRNA translation to protein may account for the disappearance of the WWOX/WOX1 family proteins in cutaneous squamous cell carcinoma cells in patients and in UVB-treated mice (24).Wild type WOX1 possesses two N-terminal WW domains (containing conserved tryptophan residues), a nuclear localization sequence and a C-terminal short-chain alcohol dehydrogenase/reductase domain (which contains a mitochondria-targeting sequence) (3). Sex steroid hormones such as estrogen and androgen activate WOX1 via Tyr 33 phosphorylation (p-WOX1) and nuclear translocation (11). Importantly, p-WOX1 is located in the mitochondria during benign prostatic hypertrophy (11). Nuclear translocation of p-WOX1 occurs when prostate cells progress toward cancerous and metastatic states (11), suggesting a critical role of WOX1 phosphorylation during prostate cancer development.We determined that WOX1 enhances the cytotoxic function of tumor necrosis factor (TNF) 4 and induces apoptosis when overexpressed (3). We also showed that in response to stress or apoptotic stimuli, WOX1 becomes phosphorylated at Tyr 33 , which allows its complex formation with activated p53 and JNK1 (25). The p53-WOX1 complex translocates to the mitochondria and nuclei to mediate apoptosis (25,26). WOX1 induces apoptosis synergistically with p53 (3,25). In contrast, JNK1 may block WOX1-induced cell death (25). Src is known to phosphorylate WOX1 at Tyr 33 (27). We also determined that Tyr 33 -phosphorylated WO...

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Merlin Neutralizes the Inhibitory Effect of Mdm2 on p53

Cited by 58 publications

References 38 publications

JCV T-antigen interacts with the neurofibromatosis type 2 gene product in a transgenic mouse model of malignant peripheral nerve sheath tumors

JCV T-antigen interacts with the neurofibromatosis type 2 gene product in a transgenic mouse model of malignant peripheral nerve sheath tumors

Merlin, a Tumor Suppressor, Interacts with Transactivation-responsive RNA-binding Protein and Inhibits Its Oncogenic Activity

WOX1 Is Essential for Tumor Necrosis Factor-, UV Light-, Staurosporine-, and p53-mediated Cell Death, and Its Tyrosine 33-phosphorylated Form Binds and Stabilizes Serine 46-phosphorylated p53

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