RGD Reference Report - Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis. - Rat Genome Database

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Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis.

Authors: Pece, S  Serresi, M  Santolini, E  Capra, M  Hulleman, E  Galimberti, V  Zurrida, S  Maisonneuve, P  Viale, G  Di Fiore, PP 
Citation: Pece S, etal., J Cell Biol 2004 Oct 25;167(2):215-21. Epub 2004 Oct 18.
RGD ID: 1334451
Pubmed: PMID:15492044   (View Abstract at PubMed)
PMCID: PMC2172557   (View Article at PubMed Central)
DOI: DOI:10.1083/jcb.200406140   (Journal Full-text)

The biological antagonism between Notch and Numb controls the proliferative/differentiative balance in development and homeostasis. Although altered Notch signaling has been linked to human diseases, including cancer, evidence for a substantial involvement of Notch in human tumors has remained elusive. Here, we show that Numb-mediated control on Notch signaling is lost in approximately 50% of human mammary carcinomas, due to specific Numb ubiquitination and proteasomal degradation. Mechanistically, Numb operates as an oncosuppressor, as its ectopic expression in Numb-negative, but not in Numb-positive, tumor cells inhibits proliferation. Increased Notch signaling is observed in Numb-negative tumors, but reverts to basal levels after enforced expression of Numb. Conversely, Numb silencing increases Notch signaling in normal breast cells and in Numb-positive breast tumors. Finally, growth suppression of Numb-negative, but not Numb-positive, breast tumors can be achieved by pharmacological inhibition of Notch. Thus, the Numb/Notch biological antagonism is relevant to the homeostasis of the normal mammary parenchyma and its subversion contributes to human mammary carcinogenesis.

Molecular Pathway Annotations    Click to see Annotation Detail View

RGD Manual Annotations

Objects Annotated

Genes (Rattus norvegicus)
Numb  (NUMB, endocytic adaptor protein)
Numbl  (NUMB-like, endocytic adaptor protein)

Genes (Homo sapiens)
NUMB  (NUMB endocytic adaptor protein)


Additional Information