Functional domains of necdin for protein–protein interaction, nuclear matrix targeting, and cell growth suppression

Taniura, Hideo; Kobayashi, Masakatsu; Yoshikawa, Kunio

doi:10.1002/jcb.20345

Cited by 41 publications

(40 citation statements)

References 22 publications

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“…Moreover, necdin is upregulated during neuronal differentiation and is thought to play a role in cell cycle arrest in terminally differentiated neurons [20,23]. Necdin has been described as a transcriptional repressor to interact with and suppress functions of various cytoplasmic and nuclear proteins such as E2F1, p53, hnRNP U and NEFA [24][25][26][27][28].…”

Section: Discussionmentioning

confidence: 99%

Negative regulation of hypoxia inducible factor‐1α by necdin

Moon

Ahn²,

Park

et al. 2005

FEBS Letters

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Hypoxia-inducible factor 1 (HIF-1) is a master transcription factor that mediates cellular and systemic homeostatic responses to reduce O 2 availability, such as erythropoiesis, angiogenesis, and glycolysis. Using the yeast two-hybrid screening system, we found that the oxygen dependent degradation (ODD) domain of HIF-1a interacts with necdin, a growth suppressor. The interaction of necdin with HIF-1a was confirmed using coimmunoprecipitation with the overexpressed HIF-1a. Biological effect of necdin on HIF-1a showed that necdin reduces the transcriptional activity of HIF-1 under hypoxia. Moreover, necdin decreased the level of the HIF-1a protein, but not that of mRNA, implying a possibility of necdin-mediated HIF-1a degradation. Furthermore, necdin has an anti-angiogenic activity in the tube formation assay and CAM assay, which might be due to the downregulation of HIF-1a. Collectively, these results suggest that necdin can be a novel negative regulator of HIF-1a stability via the direct interaction.

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Section: Discussionmentioning

confidence: 99%

Negative regulation of hypoxia inducible factor‐1α by necdin

Moon

Ahn²,

Park

et al. 2005

FEBS Letters

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“…These findings suggest that Sirt1 plays a key role in the regulation of p53 acetylation in neurons under various developmental and neuropathological conditions. Necdin, a melanoma antigen (MAGE) family protein, interacts with p53 and represses p53-mediated apoptosis in transformed cell lines (Taniura et al, 1999(Taniura et al, , 2005. Because necdin is expressed in virtually all postmitotic neurons, but not in cell lines derived from neuroblastoma, pheochromocytoma, and glioma (Aizawa et al, 1992;Uetsuki et al, 1996;Kobayashi et al, 2002), the regulation of p53 activities by endogenous necdin in postmitotic neurons is poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Necdin Regulates p53 Acetylation via Sirtuin1 to Modulate DNA Damage Response in Cortical Neurons

Hasegawa

Yoshikawa²

2008

J. Neurosci.

142

131

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Sirtuin1 (Sirt1), a mammalian homolog of yeast Sir2, deacetylates the tumor suppressor protein p53 and attenuates p53-mediated cell death. Necdin, a p53-interacting protein expressed predominantly in postmitotic neurons, is a melanoma antigen family protein that promotes neuronal differentiation and survival. In mammals, the necdin gene (Ndn) is maternally imprinted, and mutant mice carrying mutated paternal Ndn show abnormalities of neuronal development. Here we report that necdin regulates the acetylation status of p53 via Sirt1 to suppress p53-dependent apoptosis in postmitotic neurons. Double-immunostaining analysis demonstrated that necdin colocalizes with Sirt1 in postmitotic neurons of mouse embryonic forebrain in vivo. Coimmunoprecipitation and in vitro binding analyses revealed that necdin interacts with both p53 and Sirt1 to potentiate Sirt1-mediated p53 deacetylation by facilitating their association. Primary cortical neurons prepared from paternal Ndn-deficient mice have high p53 acetylation levels and are sensitive to the DNAdamaging compounds camptothecin and hydrogen peroxide. Moreover, DNA transfection per se increases p53 acetylation and apoptosis in paternal Ndn-deficient neurons, whereas small interfering RNA-mediated p53 knockdown completely blocks these changes. However, Sirt1 knockdown increases both acetylated p53 level and apoptosis in wild-type neurons but fails to affect them in paternal Ndn-deficient neurons. In organotypic forebrain slice cultures treated with hydrogen peroxide, p53 is accumulated and colocalized with necdin and Sirt1 in cortical neurons. These results suggest that necdin downregulates p53 acetylation levels by forming a stable complex with p53 and Sirt1 to protect neurons from DNA damage-induced apoptosis.

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“…6 The MAGE homology domain does not contain any regions with significant homology with other known proteins, but it has been indicated that this domain represents an important site for protein-protein interactions. 7 CT antigen expression is a rare event in most hematologic malignancies including leukemias and nonHodgkin's B-cell lymphomas. 8,9 However, MM probably represents the malignancy with the richest CT antigen expression of all human cancers and the two CT antigens most frequently expressed in MM are MAGE-A3 and MAGE-C1/CT7.…”

Section: Introductionmentioning

confidence: 99%

Cancer-testis antigens MAGE-C1/CT7 and MAGE-A3 promote the survival of multiple myeloma cells

Atanackovic¹,

Hildebrandt²,

Jadczak³

et al. 2009

Haematologica

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BackgroundMultiple myeloma is a life-threatening disease and despite the introduction of stem cell transplantation and novel agents such as thalidomide, lenalidomide, and bortezomib most patients will relapse and develop chemoresistant disease. Therefore, alternative therapeutic modes for myeloma are needed and cancer-testis antigens such as MAGE-C1/CT7 and MAGE-A3 have been suggested to represent a class of tumor-specific proteins particularly suited for targeted immunotherapies. Surprisingly, the biological role of cancer-testis genes in myeloma remains poorly understood. Design and MethodsWe performed the first investigation of the function of two cancer-testis antigens most commonly expressed in myeloma, MAGE-C1/CT7 and MAGE-A3, using an RNA interferencebased gene silencing model in myeloma cell lines. Functional assays were used to determine changes in proliferation, cell adhesion, chemosensitivity, colony formation, and apoptosis resulting from gene-specific silencing. ResultsWe show that the investigated genes are not involved in regulating cell proliferation or adhesion; however, they play an important role in promoting the survival of myeloma cells. Accordingly, knock-down of MAGE-C1/CT7 and MAGE-A3 led to the induction of apoptosis in the malignant plasma cells and, importantly, both genes were also essential for the survival of clonogenic myeloma precursors. Finally, silencing of cancer-testis genes further improved the response of myeloma cells to conventional therapies. ConclusionsCancer-testis antigens such as MAGE-C1/CT7 and MAGE-A3 play an important role in promoting the survival of myeloma cells and clonogenic precursors by reducing the rate of spontaneous and chemotherapy-induced apoptosis and might, therefore, represent attractive targets for novel myeloma-specific therapies.Key words: cancer-testis antigens, gene function, RNAi, apoptosis, tumor immunology, multiple myeloma, stem cell transplantation.Citation: Atanackovic D, Hildebrandt Y, Jadczak A, Cao Y, Luetkens T, Meyer S, Kobold S, Bartels K, Pabst C, Lajmi N, Gordic M, Stahl T, Zander AR, Bokemeyer C, promote the survival of multiple myeloma cells. Haematologica 2010;95:785-793. doi:10.3324/haematol.2009 This is an open-access paper. © F e r r a t a S t o r t i F o u n d a t i o n Cancer-testis antigens MAGE-C1/CT7 and MAGE-A3 promote the survival of multiple myeloma cells

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Functional domains of necdin for protein–protein interaction, nuclear matrix targeting, and cell growth suppression

Cited by 41 publications

References 22 publications

Negative regulation of hypoxia inducible factor‐1α by necdin

Negative regulation of hypoxia inducible factor‐1α by necdin

Necdin Regulates p53 Acetylation via Sirtuin1 to Modulate DNA Damage Response in Cortical Neurons

Cancer-testis antigens MAGE-C1/CT7 and MAGE-A3 promote the survival of multiple myeloma cells

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