Pre-NOTCH Transcription and Translation

Translation of NOTCH1 mRNA is inhibited by microRNAs miR-200B and miR-200C, which bind to the 3'UTR of NOTCH1 mRNA. Levels of miR-200B and miR-200C are decreased in pancreatic cancer cells with an EMT (epithelial to mesenchymal transition) phenotype, and the EMT phenotype is reversed by exo-genous overexpression of miR-200B/C microRNAs, suggesting that miR-200B and mir-200C may be acting as tumor suppressors. Translation of NOTCH1 mRNA is negatively regulated by MIR449 microRNAs (MIR449A, MIR449B and MIR449C), which bind to the 3'UTR of NOTCH1. Downregulation of NOTCH1 signaling by the MIR449 cluster appears to be an evolutionarily conserved mechanism involved in regulation of vertebrate multiciliogenesis. DLL1 mRNA is also a target of the MIR449 cluster. Based on studies in mice, SIRT6-mediated deacetylation of lysine residue 10 of H3 histones (removal of H3K9Ac epigenetic mark) at promoters of NOTCH1 and NOTCH4 genes inhibits transcription of NOTCH1 and NOTCH4. SIRT6-mediated downregulation of NOTCH1 and NOTCH4 may protect podocytes, kidney cells involved in blood filtering, from injury. SIRT6 is downregulated in podocytes of patients with podo-cytopathies, such as proteinuric kidney disease, and SIRT6 levels correlate with glomerular filtration rate (Liu et al. 2017).


Pre-NOTCH Transcription and Translation ↗
Stable identifier: R-HSA-1912408 Compartments: nucleoplasm, cytosol, endoplasmic reticulum membrane In humans, the NOTCH protein family has four members: NOTCH1, NOTCH2, NOTCH3 and NOTCH4. NOTCH1 protein was identified first, as the product of a chromosome 9 gene translocated in T-cell acute lymphoblastic leukemia that was homologous to Drosophila Notch (Ellisen et al. 1991). At the same time, rat Notch1 was cloned (Weinmaster et al. 1991), followed by cloning of mouse Notch1, named Motch (Del Amo et al. 1992). NOTCH2 protein is the product of a gene on chromosome 1 (Larsson et al. 1994).
NOTCH2 expression is differentially regulated during B-cell development (Bertrand et al. 2000). NOTCH2 mutations are a rare cause of Alagille syndrome (McDaniell et al. 2006). NOTCH3 is the product of a gene on chromosome 19. NOTCH3 mutations are the underlying cause of CADASIL, cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (Joutel et al. 1996). NOTCH4, the last NOTCH protein discovered, is the product of a gene on chromosome 6 (Li et al. 1998).
Nascent NOTCH peptides are co-translationally targeted to the endoplasmic reticulum for further processing, followed by modification in the Golgi apparatus, before trafficking to the plasma membrane. Endoplasmic reticulum calcium ATPases, positively regulate NOTCH trafficking, possibly by contributing to accurate folding of NOTCH precursors (Periz et al. 1999

Literature references
Gygi, SP., Liu, XS., Geng, Y., Mizeracka, K., Jirawatnotai, S., Meyer, CA. et al. (2010). NOTCH1 was cloned as a chromosome 9 gene involved in translocation t(7;9)(q34;q34.3) in several T-cell acute lymphoblastic leukemia (T-ALL) patients. The gene was found to be highly homologous to the Drosophila gene Notch and was initially named TAN-1 (translocation-associated Notch homolog). Transcripts of NOTCH1 were detected in many fetal and adult human and mouse tissues, with the highest abundance in lymphoid tissues. The translocation t(7;9)(q34;q34.3) found in a small fraction of T-ALL patients puts NOTCH1 transcription under the control of the T-cell receptor-beta (TCRB) locus, which results in expression of truncated peptides that lack the extracellular ligand binding domain and are constitutively active (reviewed by Grabher et al. 2006

Compartments: nucleoplasm
The NOTCH4 gene maps to the short arm of human chromosome 6. High levels of NOTCH4 transcript are detectable in adult heart. NOTCH4 mRNA is also found in lung and placenta, and at low levels in liver, skeletal muscle, kidney, pancreas, spleen, thymus, lymph nodes and bone marrow (Li et al. 1998). In