mardi 22 mai 2012

Mutated genes in cancer (71) – NOTCH1


In databases:

● Entrez ( 4851 or NOTCH1
● Ensembl ( ENSG00000148400
● UniProt ( P46531
● GeneCards ( NOTCH1
● HGNC ( 7881 or NOTCH1
● Enzyme Number (IUBMB): EC, EC

Gene locus:


Protein name:

Notch 1

Protein Size:

2555 amino acids; about 273 kDa


The protein encoded by NOTCH1 functions as a receptor for membrane-bound ligands of the Jagged and Delta-like families. It is involved in cell-fate determination, implementation of differentiation, proliferation and apoptotic programs.

Cancer-related alterations:

Notch1 mutations play a dual role in carcinogenesis as either a tumor suppressor or an oncogene. The role of NOTCH1 within and between cells depends on signal strength, timing, cell type, and context.

Altered NOTCH1 is a causative factor in the development of T-cell acute lymphoblastic leukemia and lymphoma (T-ALL). It is notably involved in T-ALL following translocation t(7;9)(q34;q34.3),  leading to the fusion gene NOTCH1-TRB@, in which the 3' portion of NOTCH1 is juxtaposed with the T cell receptor β (TRB@) locus. This leads to expression of truncated NOTCH1 transcripts and consequent production of dominant active, ligand-independent forms of the NOTCH1 receptor, causing T-ALL. Less than 1% of human T-ALLs exhibit the t(7;9) translocation, however, activating mutations in NOTCH1 independent of t(7;9) have been identified in more than 50% of human T-ALL.

Somatic point mutations have been found in tumors of haematopoietic and lymphoid tissue (up to 20%), oesophagus and upper aerodigestive tract, CNS, large intestine, lung, pancreas, breast. Most mutation events are substitution, with hot spots corresponding to amino acids 1575-1601.

References (open access):

The role of NOTCH1 signaling in T-ALL. Ferrando AA. Hematology Am Soc Hematol Educ Program. 2009:353-61.

Notch1 loss of heterozygosity causes vascular tumors and lethal hemorrhage in mice. Liu Z, Turkoz A, Jackson EN, Corbo JC, Engelbach JA, Garbow JR, Piwnica-Worms DR, Kopan R. J Clin Invest. 2011 Feb 1;121(2):800-8.

Characterization of Notch1 antibodies that inhibit signaling of both normal and mutated Notch1 receptors. Aste-Amézaga M, Zhang N, Lineberger JE, Arnold BA, Toner TJ, Gu M, Huang L, Vitelli S, Vo KT, Haytko P, Zhao JZ, Baleydier F, L'Heureux S, Wang H, Gordon WR, Thoryk E, Andrawes MB, Tiyanont K, Stegmaier K, Roti G, Ross KN, Franlin LL, Wang H, Wang F, Chastain M, Bett AJ, Audoly LP, Aster JC, Blacklow SC, Huber HE. PLoS One. 2010 Feb 8;5(2):e9094

Inhibition of NOTCH signaling by gamma secretase inhibitor engages the RB pathway and elicits cell cycle exit in T-cell acute lymphoblastic leukemia cells. Rao SS, O'Neil J, Liberator CD, Hardwick JS, Dai X, Zhang T, Tyminski E, Yuan J, Kohl NE, Richon VM, Van der Ploeg LH, Carroll PM, Draetta GF, Look AT, Strack PR, Winter CG. Cancer Res. 2009 Apr 1;69(7):3060-8

Tumor suppressor role of Notch-1 signaling in neuroendocrine tumors. Kunnimalaiyaan M, Chen H. Oncologist. 2007 May;12(5):535-42.

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