Pre-NOTCH Transcription and Translation

Stable Identifier
Homo sapiens
Locations in the PathwayBrowser

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).

MicroRNAs play an important negative role in translation and/or stability of NOTCH mRNAs. MicroRNAs miR-34 (miR-34A, miR-34B and mi-R34C), whose transcription is directly induced by the tumor suppressor protein p53 (Chang et al. 2007, Raver-Shapira et al. 2007, He et al. 2007, Corney et al. 2007) bind and negatively regulate translation of NOTCH1 mRNA (Li et al. 2009, Pang et al. 2010, Ji et al. 2009) and NOTCH2 mRNA (Li et al. 2009). NOTCH1 mRNA translation is also negatively regulated by microRNAs miR-200B and miR-200C (Kong et al. 2010), as well as miR-449A, miR-449B and miR-449C (Marcet et al. 2011). Translation of NOTCH3 mRNA is negatively regulated by microRNAs miR-150 (Ghisi et al. 2011) and miR-206 (Song et al. 2009). Translation of NOTCH4 mRNA is negatively regulated by microRNAs miR-181C (Hashimoto et al. 2010) and miR-302A (Costa et al. 2009).

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
PubMed ID Title Journal Year
20351093 MicroRNA-34a suppresses invasion through downregulation of Notch1 and Jagged1 in cervical carcinoma and choriocarcinoma cells Carcinogenesis 2010
17540598 Transcriptional activation of miR-34a contributes to p53-mediated apoptosis Mol Cell 2007
20495621 Epigenetically reprogramming metastatic tumor cells with an embryonic microenvironment Epigenomics 2009
9693032 Cloning, characterization, and the complete 56.8-kilobase DNA sequence of the human NOTCH4 gene Genomics 1998
1425352 Expression pattern of Motch, a mouse homolog of Drosophila Notch, suggests an important role in early postimplantation mouse development Development 1992
19773441 MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes Cancer Res 2009
1831692 TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms Cell 1991
1764995 A homolog of Drosophila Notch expressed during mammalian development Development 1991
17540599 Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis Mol Cell 2007
8878478 Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia Nature 1996
20805998 Epithelial to mesenchymal transition is mechanistically linked with stem cell signatures in prostate cancer cells PLoS One 2010
16773578 NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway Am J Hum Genet 2006
17554337 A microRNA component of the p53 tumour suppressor network Nature 2007
11187898 Notch-1 and Notch-2 exhibit unique patterns of expression in human B-lineage cells Leukemia 2000
21551231 Modulation of microRNA expression in human T-cell development: targeting of NOTCH3 by miR-150 Blood 2011
7698746 The human NOTCH1, 2, and 3 genes are located at chromosome positions 9q34, 1p13-p11, and 19p13.2-p13.1 in regions of neoplasia-associated translocation Genomics 1994
21602795 Control of vertebrate multiciliogenesis by miR-449 through direct repression of the Delta/Notch pathway Nat Cell Biol 2011
17823410 MicroRNA-34b and MicroRNA-34c are targets of p53 and cooperate in control of cell proliferation and adhesion-independent growth Cancer Res 2007
10545110 Ca(2+)-ATPase function is required for intracellular trafficking of the Notch receptor in Drosophila EMBO J 1999
19723635 MicroRNA-206 targets notch3, activates apoptosis, and inhibits tumor cell migration and focus formation J Biol Chem 2009
19714243 MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells PLoS One 2009
20080834 Involvement of epigenetically silenced microRNA-181c in gastric carcinogenesis Carcinogenesis 2010
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