Function of Drg1/Rit42 in p53-dependent Mitotic Spindle Checkpoint

Kim, Kyung‐Tae; Ongusaha, Pat P.; Hong, Young Kwan; Kurdistani, Siavash K.; Nakamura, Masafumi; Lu, Kun Ping; Lee, Sam W.

doi:10.1074/jbc.m400781200

Cited by 55 publications

(56 citation statements)

References 25 publications

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“…These data confirm our results in MCF10A cells and demonstrate that the level of NDRG1 directly regulates centrosome homeostasis. A potential interaction between NDRG1 and γ-tubulin has been previously reported as both proteins are present within the same fraction in cosedimentation assays (22). To confirm that NDRG1 directly interacts with centrosome assembly and mitotic division in vitro, a proximity ligation assay (PLA) was carried out with antibodies against NDRG1 and γ-tubulin.…”

Section: Homozygous Deletion Of Tp53 Is Mutually Exclusive With Ndrg1mentioning

confidence: 89%

“…NDRG1 encodes the 46-kDa protein, NDRG1, which is highly conserved among multicellular organisms and is ubiquitously expressed in tissues in response to cellular stress (20). Prior studies demonstrated that NDRG1 is necessary but not sufficient for p53-mediated apoptosis (21) and may play a role in spindle organization, as NDRG1 has been shown to colocalize with centrosomes (22). However, NDRG1 as a direct mediator of p53-regulated centrosome homeostasis has not been demonstrated.…”

Section: Distinct Phenotypes Of P53 Null Versus P53 R248w Heterozygousmentioning

confidence: 99%

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NDRG1 links p53 with proliferation-mediated centrosome homeostasis and genome stability

Croessmann

Wong

Zabransky

et al. 2015

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

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The tumor protein 53 (TP53) tumor suppressor gene is the most frequently somatically altered gene in human cancers. Here we show expression of N-Myc down-regulated gene 1 (NDRG1) is induced by p53 during physiologic low proliferative states, and mediates centrosome homeostasis, thus maintaining genome stability. When placed in physiologic low-proliferating conditions, human TP53 null cells fail to increase expression of NDRG1 compared with isogenic wild-type controls and TP53 R248W knockin cells. Overexpression and RNA interference studies demonstrate that NDRG1 regulates centrosome number and amplification. Mechanistically, NDRG1 physically associates with γ-tubulin, a key component of the centrosome, with reduced association in p53 null cells. Strikingly, TP53 homozygous loss was mutually exclusive of NDRG1 overexpression in over 96% of human cancers, supporting the broad applicability of these results. Our study elucidates a mechanism of how TP53 loss leads to abnormal centrosome numbers and genomic instability mediated by NDRG1.T umor protein 53 (TP53) encodes p53 and is one of the most well-studied tumor suppressor genes. Among its many functions, p53 plays a central role in apoptosis, cell cycle arrest, and maintaining genomic integrity (1-3). Normally, p53 acts as a critical cellular checkpoint monitor in response to stress such as DNA damage. This function prevents cells with aberrant or damaged DNA from proceeding through the cell cycle, allowing time to correct damaged DNA or induce apoptosis if DNA cannot be repaired. This critical role thus prevents cells with altered DNA from inappropriate cell division.Although TP53 is one of the most well described tumor suppressor genes, the mechanisms of many of its functions have not been fully elucidated. In particular, p53's role in maintaining genomic stability remains incompletely understood. It is well known that in the absence of normal p53 function, downstream effectors such as p21 are crippled and can no longer prevent aberrant cell cycling in response to DNA damage (4). However, this fact suggests that lack of p53 function is not directly responsible for genome instability, but instead that damaged DNA is allowed to inappropriately propagate through cell division if p53 function is absent (5). This mechanism would also suggest that increased cell cycling would produce more opportunities for DNA errors, and thus the absence of p53 function in this instance would allow cells with altered DNA to propagate rapidly, leading to an increased potential for producing oncogenic changes. However, many human cancers have low proliferation rates, yet still display genomic instability and aneuploidy (6). In addition, seminal studies have demonstrated that loss of TP53 has distinct functional consequences compared with TP53 missense mutations (7,8), yet both types of alterations are found in human cancers. Thus, mechanisms of how genomic instability and aneuploidy arise may differ in cancer cells with homozygous loss of TP53 versus those with heterozygous missense mu...

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Section: Homozygous Deletion Of Tp53 Is Mutually Exclusive With Ndrg1mentioning

confidence: 89%

Section: Distinct Phenotypes Of P53 Null Versus P53 R248w Heterozygousmentioning

confidence: 99%

NDRG1 links p53 with proliferation-mediated centrosome homeostasis and genome stability

Croessmann

Wong

Zabransky

et al. 2015

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

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“…Recent reports that overexpression or knockdown of NDRG1 in cultured neoplastic cells alters their proliferation, differentiation, metastasis, and apoptosis statuses (25,28,29,(55)(56)(57)(58) and that genetic mutations in the Ndrg1 gene cause Schwann cell dysfunction leading to peripheral neuropathy in both human and mouse (30 -32) imply that this inducible intracellular protein plays roles in diverse processes linked to these cellular events. Despite its widespread distribution, however, the regulatory expression and functions of NDRG1, particularly in the immune system, have been poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Impaired Mast Cell Maturation and Degranulation and Attenuated Allergic Responses in Ndrg1-Deficient Mice

Taketomi

Sunaga²,

Tanaka

et al. 2007

The Journal of Immunology

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We have previously reported that N-myc downstream regulated gene-1 (NDRG1) is an early inducible protein during the maturation of mouse bone marrow-derived mast cells (BMMCs) toward a connective tissue mast cell-like phenotype. To clarify the function of NDRG1 in mast cells and allergic responses, we herein analyzed mast cell-associated phenotypes of mice lacking the Ndrg1 gene. Allergic responses including IgE-mediated passive systemic and cutaneous anaphylactic reactions were markedly attenuated in Ndrg1-deficient mice as compared with those in wild-type mice. In Ndrg1-deficient mice, dermal and peritoneal mast cells were decreased in number and morphologically abnormal with impaired degranulating ability. Ex vivo, Ndrg1-deficient BMMCs cocultured with Swiss 3T3 fibroblasts in the presence of stem cell factor, a condition that facilitates the maturation of BMMCs toward a CTMC-like phenotype, displayed less exocytosis than replicate wild-type cells after the cross-linking of FcεRI or stimulation with compound 48/80, even though the exocytotic response of IL-3-maintained, immature BMMCs from both genotypes was comparable. Unlike degranulation, the production of leukotriene and cytokines by cocultured BMMCs was unaffected by NDRG1 deficiency. Taken together, the altered phenotypes of Ndrg1-deficient mast cells both in vivo and ex vivo suggest that NDRG1 has roles in the terminal maturation and effector function (degranulation) of mast cells.

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“…Rit42 seems to play a role in the regulation of microtubule dynamics and the maintenance of euploidy (58). Rit42 is known to be down-regulated during colon and prostate tumor progression (59,60).…”

Section: Microtubule Motor Proteins and Spindle Checkpoint Componentsmentioning

confidence: 99%

Microtubule-Associated Proteins as Targets in Cancer Chemotherapy

Bhat

Setaluri

2007

Clinical Cancer Research

179

142

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Natural and synthetic compounds that disrupt microtubule dynamics are among the most successful and widely used cancer chemotherapeutic agents. However, lack of reliable markers that predict sensitivity of cancers to these agents and development of resistance remain vexing issues. There is accumulating evidence that a family of cellular proteins that are associated with and alter the dynamics of microtubules can determine sensitivity of cancer cells to microtubuletargeting agents and play a role in tumor cell resistance to these agents. This growing family of microtubule-associated proteins (MAP) includes products of oncogenes, tumor suppressors, and apoptosis regulators, suggesting that alteration of microtubule dynamics may be one of the critical events in tumorigenesis and tumor progression. The objective of this review is to integrate the knowledge on these seemingly unrelated proteins that share a common function and examine their relevance to microtubule-targeting therapies and highlight MAPs-tubulin-drug interactions as a novel avenue for new drug discovery. Based on the available evidence, we propose that rational microtubule-targeting cancer therapeutic approaches should ideally include proteomic profiling of tumor MAPs before administration of microtubule-stabilizing/destabilizing agents preferentially in combination with agents that modulate the expression of relevant MAPs.

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Function of Drg1/Rit42 in p53-dependent Mitotic Spindle Checkpoint

Cited by 55 publications

References 25 publications

NDRG1 links p53 with proliferation-mediated centrosome homeostasis and genome stability

NDRG1 links p53 with proliferation-mediated centrosome homeostasis and genome stability

Impaired Mast Cell Maturation and Degranulation and Attenuated Allergic Responses in Ndrg1-Deficient Mice

Microtubule-Associated Proteins as Targets in Cancer Chemotherapy

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