Deficiency of tumor suppressor NDRG2 leads to attention deficit and hyperactive behavior

Li, Yan; Yin, Anqi; Sun, Xin; Zhang, Ming; Zhang, Jianfang; Wang, Ping; Xie, Rou‐Gang; Li, Wen; Fan, Ze; Zhu, Yuanyuan; Wang, Han; Dong, Hailong; Wu, Sihan; Xiong, Lize

doi:10.1172/jci94455

Cited by 39 publications

(35 citation statements)

References 77 publications

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“…The aforementioned results prompted us to uncover how Ndrg2 loss caused the transcriptional repression of E-cadherin. However, the current studies didn’t support the concept of NDRG2 as a transcriptional regulator per se[9, 17, 18]. It’s reasonable for us to further analyze whether Ndrg2 deficiency alters the expression of key transcriptional regulators of E-cadherin, such as Snail, Slug and ZEB1/2 etc[19, 20].…”

Section: Resultsmentioning

confidence: 99%

NDRG2 Regulates Adherens Junction Integrity to Restrict Colitis and Tumorigenesis

Wei

Shen

et al. 2018

Preprint

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Paracellular barriers play an important role in the pathogenesis of IBDs and maintain gut homeostasis. N-myc downstream-regulated gene 2 (NDRG2) has been reported to be a tumor suppressor gene and inhibits colorectal cancer metastasis. However, whether NDRG2 affects colitis initiation and colitis-associated colorectal cancer is unclear. Here, We found that intestine-specific Ndrg2 deficiency caused mild spontaneous colitis with ageing, aggravated DSS and TNBS induced colitis, increased AOM-DSS induced colitis-associated tumor. Ndrg2 loss led to adherens junction (AJ) structure destruction via E-cadherin expression attenuation, resulting in diminished epithelial barrier function and increased intestinal epithelial permeability. Mechanistically, NDRG2 enhancing the interaction of E3 ligase FBXO11 with Snail, the repressor of E-cadherin, to promote Snail degradation by ubiquitination, and maintained E-cadherin expression. In human ulcerative colitis patients, reduced NDRG2 expression is positively correlated with severe inflammation. These findings demonstrate that NDRG2 is an essential colonic epithelial barrier regulator and plays important role in gut homeostasis maintenance and colitis-associated tumor development.SUMMARYAdherens junctoin (AJ) as the key part of intestinal epithelial barrier plays important role in the pathogenesis of IBDs. Intestinal specific Ndrg2 loss attenuates E-cadherin expression and disrupts the integrity of AJ structure which is feasible for colitis and tumor development.

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Section: Resultsmentioning

confidence: 99%

NDRG2 Regulates Adherens Junction Integrity to Restrict Colitis and Tumorigenesis

Wei

Shen

et al. 2018

Preprint

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“…NDRG family members are abundantly expressed in brain tissue; therefore, the significant functions of these NDRG2 family members in the central nervous system were anticipated and have been confirmed with NDRG gene knockout micebased studies [69][70][71]. NDRG1 deficiency leads to a progressive demyelinating in the peripheral nerves, suggesting that NDRG1 is involved in the maintenance of and axonal survival and myelin sheath structure [69].…”

Section: Ndrg2 In Brain Tumors and Other Nervous System Diseasesmentioning

confidence: 96%

“…NDRG1 deficiency leads to a progressive demyelinating in the peripheral nerves, suggesting that NDRG1 is involved in the maintenance of and axonal survival and myelin sheath structure [69]. Ndrg2 −/− mice exhibited typical ADHD-like behaviors, including hyperactivity, impulsivity, and inattention, as well as impaired memory [70]. Ndrg4 −/− mice showed impaired cognition and increased susceptibility to ischemic stroke, indicating that NDRG4 has a potential neuroprotective effect [71].…”

Section: Ndrg2 In Brain Tumors and Other Nervous System Diseasesmentioning

confidence: 99%

N-Myc Downstream-Regulated Gene 2 (NDRG2) as a Novel Tumor Suppressor in Multiple Human Cancers

Zhang¹,

Li²,

Shen³

et al. 2019

Genes and Cancer

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N-myc downstream-regulated gene 2 (NDRG2) was identified as a novel tumor suppressor gene in regulating the proliferation, differentiation, apoptosis and metastasis of multiple cancer types. Consistent with this finding, we and other groups observed the decreased NDRG2 expression in multiple human cancer cell lines and tumors, including breast cancer, colorectal cancer, and cervical cancer. We identified NDRG2 as a stress sensor for hypoxia, DNA damage stimuli and endoplasmic reticulum stress (ERS). Our recent data showed that NDRG2 could promote the differentiation of colorectal cancer cells. Interestingly, we found that reduced NDRG2 expression was a powerful and independent predictor of poor prognosis of colorectal cancer patients. Furthermore, NDRG2 can inhibit epithelial-mesenchymal transition (EMT) by positively regulating E-cadherin expression. Moreover, NDRG2-deficient mice show spontaneous development of various tumor types, including T-cell lymphomas, providing in vivo evidence that NDRG2 functions as a tumor suppressor gene. We believe that NDRG2 is a novel tumor suppressor and might be a therapeutic target for cancer treatment.Genes and Cancer 2 carcinoma cells [8]. Moreover, NDRG2-deficient mice show spontaneous development of various tumor types, providing in vivo evidence that NDRG2 functions as a tumor suppressor gene. In this chapter, we will introduce the recent findings of NDRG2 as tumor suppressor in vitro and in vivo, and also the detailed mechanism. NDRG2 as a hypoxia and DNA damage responderOur group firstly identified NDRG2 as a protein containing an acyl-carrier protein (ACP)-like domain. The gene was cloned from differentially expressed genes between glioblastoma and normal brain tissues using PCR-based subtractive hybridization in 2003. NDRG2, NDRG1, NDRG3, and NDRG4 comprise the NDRG gene family [1] and share approximately 59-68% homology. Additionally, NDRG family members display over 92% homology between humans and mice.The expression and cellular localization of NDRG2 were altered following exposure to different stresses, supporting the role of NDRG2 as a cellular stress sensor. Wang et al. found that NDRG2 expression was markedly upregulated in several cancer cell lines exposed to hypoxic conditions or similar stresses at both the mRNA and protein levels [9]. Hypoxia-inducible factor-1α (HIF-1α) can directly bind to hypoxia response elements (HREs) in the NDRG2 promoter, thus upregulating NDRG2 expression under hypoxia. Importantly, enforcing the expression of NDRG2 can strongly increase the apoptosis of cancer cells. Alternatively, NDRG2 can translocate from the cytoplasm to the nucleus under DNA damage stress. However, no explicit nuclear localization signal (NLS) sequence has been identified in the NDRG2 protein. Although NLSs are the most common type of nuclear import elements, other mechanisms may also be involved in NDRG2 translocation. For example, Liu et al. and Cao et al. confirmed that NDRG2 was upregulated by p53 or adriamycin (ADR) treatment [10,11]. Thus, NDRG2 can tra...

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“…NDRG2 was reported as an earlystage stress response gene, and its expression is upregulated under excitotoxic conditions in the brain, including ischemia [22], hemorrhage [23], trauma [24], and Alzheimer's disease. To evaluate the potential physiological or pathological roles of NDRG2 in the brain, we generated NDRG2 knockout (Ndrg2 −/− ) mice [25]. These mice are susceptible to cerebral ischemia and exhibit increased interstitial glutamate levels in the brain, suggesting that NDRG2 plays an essential role in controlling glutamate excitotoxicity.…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

NDRG2 Protects the Brain from Excitotoxicity by Facilitating Interstitial Glutamate Uptake

Yin

Guo

Tao

et al. 2019

Transl. Stroke Res.

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Glutamate is a prominent neurotransmitter responsible for excitatory synaptic transmission and is taken up by sodium-dependent excitatory amino acid transporters (EAATs) on astrocytes to maintain synaptic homeostasis. Here, we report that N-myc downstream regulated gene 2 (NDRG2), a known tumor suppressor, is required to facilitate astroglial glutamate uptake and protect the brain from glutamate excitotoxicity after ischemia. NDRG2 knockout (Ndrg2 −/−) mice exhibited an increase in cerebral interstitial glutamate and a reduction in glutamate uptake into astrocytes. The ability of NDRG2 to control EAAT-mediated glutamate uptake into astrocytes required NDRG2 to interact with and promote the function of Na + /K +-ATPase β1, which could be disrupted by a Na + /K +-ATPase β1 peptide. The deletion of NDRG2 or treatment with the Na + /K +-ATPase β1 peptide significantly increased neuronal death upon a glutamate challenge and aggravated brain damage after ischemia. Our findings demonstrate that NDRG2 plays a pivotal role in promoting astroglial glutamate uptake from the interstitial space and protecting the brain from glutamate excitotoxicity.

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Deficiency of tumor suppressor NDRG2 leads to attention deficit and hyperactive behavior

Cited by 39 publications

References 77 publications

NDRG2 Regulates Adherens Junction Integrity to Restrict Colitis and Tumorigenesis

NDRG2 Regulates Adherens Junction Integrity to Restrict Colitis and Tumorigenesis

N-Myc Downstream-Regulated Gene 2 (NDRG2) as a Novel Tumor Suppressor in Multiple Human Cancers

NDRG2 Protects the Brain from Excitotoxicity by Facilitating Interstitial Glutamate Uptake

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