Physical Interaction of p73 with c-Myc and MM1, a c-Myc-binding Protein, and Modulation of the p73 Function

Watanabe, Kenji; Ozaki, Toshinori; Nakagawa, Takahito; Miyazaki, Koichi; Takahashi, Masato; Hosoda, Mitsuchika; Hayashi, Syunji; Todo, Satoru; Nakagawara, Akira

doi:10.1074/jbc.m111281200

Cited by 69 publications

(54 citation statements)

References 57 publications

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“…The absence of mutations in these polyp samples was not unexpected. It is widely accepted that c-MYC has effects beyond induction of proliferation; it also activates apoptotic pathways, possibly to safeguard against upregulation of c-MYC in the absence of appropriate growth signals, perhaps through interactions with Bin-1, pRb, p53, and p73, and through activation of p53 expression (9,(27)(28)(29). In colorectal cancer, p53 mutation or inactivation is a late event in tumorigenesis (25); therefore, overexpression of c-MYC may be expected to occur later in a tumor's development, after such apoptotic checkpoints have been compromised.…”

Section: Human Colon Adenoma Samples Do Not Carry the Mutations Found Inmentioning

confidence: 99%

RETRACTED: Mutations in the G-quadruplex silencer element and their relationship to c-MYC overexpression, NM23 repression, and therapeutic rescue

Grand

Powell

Nagle

et al. 2004

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

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We have demonstrated that a parallel G-quadruplex structure in the c-MYC promoter functions as a transcriptional repressor element. Furthermore, a specific G-to-A mutation in this element results in destabilization of the G-quadruplex repressor element and an increase in basal transcriptional activity. To validate this model in an in vivo context, we have examined the sequence of this region in human colorectal tumors and the surrounding normal tissue. We have found that ≈30% of tumors contain one of two specific G-to-A mutations, not present in the surrounding normal tissue, that destabilize the parallel G-quadruplex, which would be expected to give rise to abnormally high expression of c-MYC in these cells. In contrast, G-quadruplex-disruptive mutations were absent in 20 colon adenomas, suggesting that these mutations occur late in tumorigenesis. We have also demonstrated that these same mutations are found in established colorectal cell lines. NM23-H2 levels are lower in cancer tissues and cell lines that harbor these mutations. In cells with repressed levels of NM23-H2, the mutated and destabilized G-quadruplex silencer element can be reinstated by the addition of G-quadruplex-stabilizing compounds, providing an opportunity for therapeutic intervention for patients carrying these mutations

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Section: Human Colon Adenoma Samples Do Not Carry the Mutations Found Inmentioning

confidence: 99%

RETRACTED: Mutations in the G-quadruplex silencer element and their relationship to c-MYC overexpression, NM23 repression, and therapeutic rescue

Grand

Powell

Nagle

et al. 2004

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

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“…The unique carboxyl-terminal region of p73␣ has the function to modulate DNAbinding and transactivation activities. In addition this region contains both a proline-rich area and the SAM domain known as interacting domains, and has been reported to be a platform for the binding of multiple proteins, such as MM1 (a nuclear c-myc-binding protein) (49), SUMO-1 (small ubiquitin-like modifier 1) (50), RACK1 (receptor for activated C kinase) (51), and NF-Y transcription factor (52). Whereas binding of MM1 enhances the transcriptional activity of p73␣, c-myc and RACK1 antagonize it.…”

Section: Discussionmentioning

confidence: 99%

Full-length p73α Represses Drug-induced Apoptosis in Small Cell Lung Carcinoma Cells

Nyman

Sobczak-Pluta

Vlachos

et al. 2005

Journal of Biological Chemistry

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The p73 gene, a member of the p53 family, encodes several variants through differential splicing and use of alternative promoters. At the NH 2 terminus, two different promoters generate the fulllength and the ⌬N isoforms, with or without the transactivating domain. At the COOH terminus, seven isoforms generated through alternative splicing have been cloned. Previous studies have demonstrated that ⌬Np73 isoforms exert a dominant-negative effect on p73 by blocking their transactivation activity and hence the ability to induce apoptosis. Considerable efforts are made to identify the functional diversity of the COOH-terminal p73 variants. In this study, we found that p73␣ inhibited drug-induced apoptosis in small cell lung carcinoma cells, whereas p73␤ promoted it. p73␣ prevented Bax activation, mitochondrial dysfunction, and caspase activation. In addition, p73␣ was also able to reduce apoptosis induced by the BH3-only protein PUMA (p53 up-regulated modulator of apoptosis). Furthermore, we discovered that p73␣ is able to inhibit the pro-apoptotic effect of p73␤, demonstrating the existence of equilibrium between these two p73 isoforms. In conclusion, the reported overexpression of p73␣ in certain tumor types, and our findings that p73␣ exerts anti-apoptotic functions, indicate a potential oncogenic activity for p73.

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“…5). It has been shown that the p73 protein is regulated by diverse factors, including MDM2, MDMX, p300/ CBP, Amphiphysin IIb-1, ASPP (apoptosis-stimulated proteins of p53) 1 and 2, c-Abl (cellular Abelson oncogene), c-Myc, CTF2 (CCAATbinding transcription factor 2), Cyclin G, HCV (hepatitis C virus protein), MM1, PMS2 (mismatch-repair protein s2), WT1 (Wilms tumor protein), and YAP (Yes-associated protein) (15,16,(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43). Among these regulators, MDM2 is a well known repressor of p73 and p53, but its inhibitory effect on p73 does not involve degradation.…”

Section: P19mentioning

confidence: 99%

p19 Interacts with and Activates p73 by Involving the MDM2 Protein

Jeong

Bae

Kim

et al. 2006

Journal of Biological Chemistry

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p73␤ is a structural and functional homologue of p53, a tumor suppressor gene. In this study, we identified a novel p73␤-binding protein, p19ras , by the yeast two-hybrid screening method. Alternative splicing of the proto-oncogene H-ras pre-mRNA has led to two distinct transcripts, p19 ras and p21 ras . In both endogenous and overexpressed systems, we confirmed that p19 ras binds to full-length p73␤ in vivo and in vitro. Coexpression of p19 ras with p73␤ stimulated the transcriptional activity of p73␤. Ras proteins are known to be small membrane-localized guanine nucleotide-binding proteins. However, unlike other Ras proteins, p19 ras is localized in the nucleus and the cytosol and its interaction with p73␤ occurred exclusively in the nucleus. Oncogenic MDM2 (mouse double minutes 2) is a known repressor of p73 transcriptional activity. In this study, when p19 ras was bound to MDM2, it further inhibited the association of MDM2 to the p73␤ protein. In addition, p19 ras abolished MDM2-mediated transcriptional repression of p73␤. Therefore, this study presents a novel pathway of Ras signaling that occurs in the nucleus, involving p19 ras and p73␤. Furthermore, a p19 rasmediated novel regulatory mechanism of p73 involving the MDM2 protein is described.More than a decade after the recognition of p53 as a major tumor suppressor, two p53 homologues, p73 and p63, were identified (1). The significant sequence homology between p73 and p53 suggests that the two proteins have similar functions as transcriptional factors. p73 not only activates the transcription of p53 target genes, but it also induces apoptosis and cell cycle arrest, like p53 (2, 3). However, a number of differences between p73 and p53 have been reported. p73 transactivates only certain p53-responsive genes (4, 5). Viral oncoproteins that bind to p53 and inhibit its activity do not interact with p73 (6, 7). Furthermore, the expression level of p73 is not affected by exposure to DNA-damaging agents that increase p53 levels, indicating that the two proteins have distinct cellular functions (8).MDM2 (mouse double minutes 2) is an oncoprotein that is overexpressed in many human cancers (9). It is well established that MDM2 inactivates p53 activity through monomeric ubiquitination of lysine residues of p53 (10 -12). In contrast, although p73 binds to MDM2 as well, their interaction does not lead to the proteosomal degradation of p73 (13). Nevertheless, the binding of p73 to MDM2 results in a dramatic inhibition of p73 transactivating activity (14). It has been shown that the binding to a cofactor, p300/CREB-binding protein (CBP), 3 is required for the transcriptional activity of p73 and that MDM2 competes with p73 for the p300/CBP (15). In a previous report, we demonstrated that Amphiphysin IIb-1 sequesters nascent p73 proteins in the cytoplasm and thus inhibits its transcriptional activity (16).Using the yeast two-hybrid screening method, we identified a novel p73␤-binding protein, p19ras , which is an alternative splicing variant of c-H-ras (17). Proto-oncogen...

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Physical Interaction of p73 with c-Myc and MM1, a c-Myc-binding Protein, and Modulation of the p73 Function

Cited by 69 publications

References 57 publications

RETRACTED: Mutations in the G-quadruplex silencer element and their relationship to c-MYC overexpression, NM23 repression, and therapeutic rescue

RETRACTED: Mutations in the G-quadruplex silencer element and their relationship to c-MYC overexpression, NM23 repression, and therapeutic rescue

Full-length p73α Represses Drug-induced Apoptosis in Small Cell Lung Carcinoma Cells

p19 Interacts with and Activates p73 by Involving the MDM2 Protein

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