Disease relevance of NODAL

• Overexpression of Nodal in normal trophoblast cells (HTR8/SVneo) and several choriocarcinoma cell lines resulted in a significant decrease in the number of metabolically active cells [1].
• We have recently shown that Nodal, a member of transforming growth factor-beta superfamily, and its receptor, activin receptor-like kinase 7 (ALK7), inhibit proliferation and induce apoptosis in human epithelial ovarian cancer cell lines [2].
• We also discuss recent data showing that Nodal also acts indirectly through stimulation of the secreted protein Cerberus, which is a member of the differential-screening selected aberrant in neuroblastoma (DAN) family of secreted proteins [3].
• RESULTS: Nodal involvement correlated with PDGF-A and TGF-beta1 mRNA expression in early and advanced carcinomas, respectively [4].
• Melanoma pathogenesis and Nodal: a partial picture [5]?

High impact information on NODAL

• In addition, Nodal signaling is dependent on coreceptors of the EGF-CFC family and antagonized by the Lefty and Cerberus families of secreted factors [6].
• Additional modulators of Nodal signaling include convertases that regulate the generation of the mature signal, and factors such as Arkadia and DRAP1 that regulate the cellular responses to the signal [6].
• TGFss signals belonging to the Nodal family set up the embryonic axes, induce mesoderm and endoderm, pattern the nervous system, and determine left-right asymmetry in vertebrates [6].
• These studies demonstrate that Nodal signaling is modulated at almost every level to precisely orchestrate tissue patterning during vertebrate embryogenesis [6].
• A component of the ARC/Mediator complex required for TGF beta/Nodal signalling [7].

Chemical compound and disease context of NODAL

• Incidence of Dual AV Node Physiology Following Termination of AV Nodal Reentrant Tachycardia by Adenosine-5'-Triphosphate: A Comparison with Drug Administration in Sinus Rhythm [8].

Biological context of NODAL

• CER1 upregulation in human ES cells leads to Nodal signaling inhibition associated with differentiation of human ES cells [9].
• Ectopic expression of both proteins in zebrafish embryos causes cyclopia, a phenotype that can arise from a defect in mesendoderm patterning mediated by the Nodal signaling pathway [10].
• We propose a model in which Cripto has dual roles as a coreceptor as well as a coligand for Nodal and that this signaling interaction with Nodal is regulated by an unusual form of glycosylation [11].
• Overexpression of Nodal and ALK7-ca induced apoptosis in trophoblast cells as determined by Hoechst staining, flow cytometry, and caspase-3 Western blotting [1].
• In addition, Nodal and ALK7-ca also inhibited cell proliferation as measured by 5-bromo-2'-deoxyuridine (BrdU) assays [12].

Anatomical context of NODAL

• During early embryogenesis, the TGF-beta-like protein Nodal (or a Nodal-related ortholog) is expressed by the left lateral plate mesoderm and provides essential LR cues to the developing organs [13].
• Here, we have analysed how the FGF and BMP pathways interact with Nodal signalling during the process of endoderm formation [14].
• Both DVE and primitive streak formation, and hence positioning of the AP axis, rely on the TGFbeta family member Nodal and its proprotein convertases Furin and Pace4 [15].
• BMP signaling positively regulates Nodal expression during left right specification in the chick embryo [16].
• We conclude that Nodal is already activated in primitive endoderm, but induces a functional DVE only after promoting the expansion of embryonic VE and pluripotent progenitor cells in the epiblast [15].

Associations of NODAL with chemical compounds

• In addition, Nodal and ALK7-ca decreased the number of proliferating cells as measured by bromodeoxyuridine assays [1].
• Recently, we demonstrated that Nodal mRNA and several ALK7 transcripts are expressed in human placenta throughout pregnancy (Roberts, H. J., Hu, S., Qiu, Q., Leung, P. C. K., Cannigia, I., Gruslin, A., Tsang, B., and Peng, C. (2003) Biol. Reprod. 68, 1719-1726) [1].
• In particular, we discuss the role of the Shh pathway in this process and on its interactions with the FGF, retinoic acid and Nodal pathways and other information cascades that modify its effects [17].
• Erratum: Nodal Cooper-pair stabilized phase dynamics in granular d-wave superconductors [Phys. Rev. Lett. 92, 037004 (2004)] [18].

Regulatory relationships of NODAL

• Taken together, these observations establish that Smad2/3 is activated in undifferentiated hESCs and required for the expression of genes controlling Nodal signaling [19].
• Nodal and Nodal-related proteins activate the Activin-like signal pathway and play a key role in the formation of mesoderm and endoderm in vertebrate development [20].

Other interactions of NODAL

• This study shows that nodal and the inhibitors of Nodal signaling, lefty-A and lefty-B, are down-regulated very early upon differentiation [19].
• Moreover, there appears to be cross-talk between inhibition of GSK3, a hallmark of Wnt signaling and the Activin/Nodal pathway [19].
• Recently, we have cloned four transcripts of human activin receptor-like kinase 7 (ALK7), a type I receptor for Nodal [12].
• Using a luciferase reporter assay, we found that Cripto has activities consistent with its being a coreceptor for Nodal [11].
• Taken together, this study demonstrates for the first time that Nodal, acting through ALK7 and Smad2/3, inhibits proliferation and induces apoptosis in human trophoblast cells [1].

Analytical, diagnostic and therapeutic context of NODAL

• However, Cripto can also function as a secreted signaling factor in cell coculture assays, suggesting that it may also act as a coligand for Nodal [11].
• RESULTS: Nodal status, T stage, and grade were the only prognostic factors independently significant for both disease-free survival and OS [21].
• More Extensive Nodal Dissection Improves Survival for Stages I to III of Colon Cancer: A Population-Based Study [22].
• CONCLUSIONS: Nodal basin failure after lymphadenectomy in patients who underwent previous biopsy of a histologically positive SLN is primarily a function of aggressive locoregional disease rather than of contamination from previous surgery [23].
• In regard to: Lee RJ, et al. Nodal basin recurrence following lymph node dissection for melanoma: implications for adjuvant radiotherapy. Int J. Radiat oncol biol phys 2000;46:467-474 [24].

References