Disease relevance of NDRG1

• We initially demonstrated that the expression of NDRG1 is enhanced in primary human trophoblasts exposed to hypoxia [1].
• In addition, NDRG1 may be a putative tumor metastasis promoter gene and is regarded as one of the molecular biological markers that can forecast early metastasis of CRCs [2].
• At the same time, the correlations of NDRG1 with sex, age of patients and histological types of colorectal carcinomas were observed [2].
• Among the esophageal cancer tissues, NDRG1 mRNA expression was significantly lower in tumors of more advanced pathological stage (0-I vs. II-IV; P = 0.0027) and local tumor invasion (T1-2 vs. T3-4; P = 0.0136) [3].
• Decreased expression of NDRG1 is correlated with tumor progression and poor prognosis in patients with esophageal squamous cell carcinoma [3].

Psychiatry related information on NDRG1

• The authors report a case that offers insight into the diagnostic challenges of "Munchausen Syndrome by Proxy." Initial presentation with history of fever and later with intractable vomiting led to invasive and expensive diagnostic evaluation before confirming the diagnosis [4].
• RESULTS: Proxy respondents provided levels of complete information similar to index cases and controls for height and weight; occupational physical activity; consumption of coffee, alcohol, and cigarettes; and family history of cancer [5].
• The importance of transference and countertransference in Munchausen Syndrome by Proxy [6].
• Repeated false allegations of sexual abuse presenting to sheriffs: when is it Munchausen by Proxy [7]?
• There would seem to be three motives for research into Munchausen Syndrome by Proxy (MSBP) abuse; first to enhance treatment; second to enhance our understanding of the psychopathology of those who carry out the abuse; and third to find interventions to prevent its occurrence [8].

High impact information on NDRG1

• RESULTS: In the normal liver, hepatocytes expressed E-cadherin and a 129-kilodalton cadherin identified by the anti-N-cadherin antibody GC4 [9].
• Its induction also depends on the cognate host disease resistance gene RPS2 and the NDR1 gene that is required for RPS2-specified resistance [10].
• NDRG1 is ubiquitously expressed and has been proposed to play a role in growth arrest and cell differentiation, possibly as a signaling protein shuttling between the cytoplasm and the nucleus [11].
• Taken together, these findings point to NDRG1 having a role in the peripheral nervous system, possibly in the Schwann-cell signaling necessary for axonal survival [11].
• NDRG1 is an intracellular protein that is induced under a number of stress and pathological conditions, and it is thought to be associated with cell growth and differentiation [12].

Chemical compound and disease context of NDRG1

• 17Beta-estradiol induces down-regulation of Cap43/NDRG1/Drg-1, a putative differentiation-related and metastasis suppressor gene, in human breast cancer cells [13].
• We report the structural and biophysical consequences of cysteine substitutions in the DNA-binding replication terminator protein (RTP) of Bacillus subtilis, that resulted in an optimised RTP mutant suitable for structural studies [14].

Biological context of NDRG1

• RNA interference and inducible gene expression approaches suggest that NDRG1 is necessary but not sufficient for p53-mediated caspase activation and apoptosis [15].
• Importantly, we found a similar increase in NDRG1 expression in placental samples derived from either singleton gestations complicated by intrauterine growth restriction or from dizygotic twin gestation where one twin exhibited growth restriction [1].
• The promoter region of the NDRG1 gene contains a p53 binding site that confers p53-dependent transcriptional activation via a heterologous reporter [15].
• The expression of the protein N-myc down-regulated gene 1 (NDRG1) is regulated during cell proliferation, differentiation, and in response to stress [1].
• NDRG1 is necessary for p53-dependent apoptosis [15].

Anatomical context of NDRG1

• In contrast, lentivirus-driven short interfering RNA-mediated silencing of NDRG1 diminished trophoblast viability and differentiation [1].
• A nonsense mutation in the NDRG1 gene has been reported to be causative for hereditary motor and sensory neuropathy-Lom (HMSNL), indicating that NDRG1 functions in the peripheral nervous system necessary for axonal survival [16].
• Moreover, enforced HIF-1alpha expression also elevated NDRG1 mRNA and protein in U937 cells [17].
• These threonines were phosphorylated in NDRG1 in the liver, lung, spleen and skeletal muscle of wild-type mice, but not in SGK1-/- mice [18].
• Knock-down of SGK1 in HeLa cells using small interfering RNA also suppressed phosphorylation of the threonine residues in the repeat region of NDRG1 [18].

Associations of NDRG1 with chemical compounds

• Exploitation of KESTREL to identify NDRG family members as physiological substrates for SGK1 and GSK3 [18].
• Homocysteine did not induce Cap43 in a number of cell lines, with the exception of human endothelial cells [19].
• Activation of signaling pathways with vanadate did not induce Cap43 nor did trifluoperazine block its induction by nickel; however, okadaic acid, a serine/threonine phosphatase inhibitor, induced Cap43 to a greater extent than any nickel compound tested [19].
• This clone, designated rit42 (reduced in tumor, 42 kDa), was previously isolated as a homocysteine-inducible gene in human endothelial cells (RTP), and the same or a highly related androgen-responsive gene in mouse has also been identified [20].
• A synergistic induction of Drg-1 expression was seen with the combination of tributyrin and a low dose of 5'-aza-2'-dexoycytidine (100 nM), an inhibitor of DNA methylation [21].

Physical interactions of NDRG1

• Together, our data indicate that NDRG1 interacts with SIRT1/p53 signaling to attenuate hypoxic injury in human trophoblasts [1].

Enzymatic interactions of NDRG1

• SGK1 also phosphorylated the related NDRG1 isoform at Thr328, Ser330 and Thr346 (equivalent to Thr330, Ser332 and Thr348 of NDRG2), as well as Thr356 and Thr366 [18].

Regulatory relationships of NDRG1

• Furthermore, NDRG1 expression was regulated by the activity of SIRT1 (Sir2-like protein 1), which promotes cell survival [1].
• In the study reported here, we isolated a p53-regulated gene named NDRG1 (N-Myc down-regulated gene 1) [15].
• Of these 9 genes, expression of the Cap43 gene was specifically downregulated by VHL [22].
• Through an earlier gene expression study, we identified N-Myc downregulated gene 1 (NDRG1) to be significantly highly expressed in hepatocellular carcinoma compared to nontumor liver [23].
• Using differential display, we find the previously described growth-inhibitory gene Ndrg1 is strongly repressed in all tested Nb cell lines bearing N-myc amplification, as well as in a neuroepithelioma line with amplified c-myc [24].

Other interactions of NDRG1

• These two genes, together with NDRG1 and a previously deposited cDNA (designated NDRG2), constitute the NDRG gene family [25].
• Characterization of the human NDRG gene family: a newly identified member, NDRG4, is specifically expressed in brain and heart [25].
• Consistent with these results, NDRG1 reduced the expression level of p53 in trophoblasts cultured in standard or hypoxic conditions [1].
• NDRG1 (N-Myc downstream regulated) is upregulated during cell differentiation, repressed by N-myc and c-myc in embryonic cells, and suppressed in several tumor cells [16].
• Expression analysis of the two selected ER stress responsive genes, NDRG1 and HERPUD1 in primary CaPs revealed a significantly reduced tumor associated expression [26].

Analytical, diagnostic and therapeutic context of NDRG1

• Sequence analysis of NDRG1 in 104 CMT patients of diverse ethnicity identified one novel disease-causing mutation, IVS8-1G>A (g.2290787G>A), which affects the splice-acceptor site of IVS8 and results in the skipping of exon 9 [27].
• Western blot analysis showed that RTP expression was induced in human umbilical vein endothelial cells under conditions causing endoplasmic reticulum stress [28].
• By immunohistochemistry, we observed that NDRG1 was highly expressed in well-differentiated cells of pancreatic cancer, whereas the poorly differentiated tumour cells were negative [29].
• Immunofluorescence analysis of a FLAG epitope-tagged RTP/rit42 protein revealed a cytoplasmic localization pattern with redistribution to the nucleus upon DNA damage [20].
• Northern blot analysis revealed that RTP gene expression was induced in HUVEC after 4 h incubation with homocysteine [30].

References