NOTCH3 Intracellular Domain Regulates Transcription

NOTCH3 coactivator complex induces transcription of the well established NOTCH target genes HES1, HEYL (Maier and Gessler 2000, Geimer Le Lay et al. 2014), HES5 (Lin te al. 2002, Shimizu et al. 2002), and HEY2.

NOTCH3 positively regulates transcription of the pre-T-cell receptor alpha chain (PTCRA, commonly known as pT-alpha or pre-TCRalpha). IK1, splicing isoform of the transcription factor Ikaros (IKZF1), competes with RBPJ for binding to the PTCRA promoter and inhibits PTCRA transcription. NOTCH3, through pre-TCR signaling, stimulates expression of the RNA binding protein HuD, which promotes splicing of IKZF1 into dominant negative isoforms. These dominant negative isoforms of IKZF1 heterodimerize with IK1, preventing its binding to target DNA sequences and thus contributing to sustained transcription of PTCRA (Bellavia et al. 2007, reviewed by Bellavia, Mecarrozzi, Campese, Grazioli, Gulino and Screpanti 2007).

NOTCH3-triggered pre-TCR-signaling downregulates the activity of the transcription factor TCF3 (E2A), through ERK-dependent induction of ID1. Inhibition of TCF3-mediated transcription downstream of NOTCH3 contributes to development of T-cell lymphomas in transgenic mice expressing NICD3. Activation of ERKs downstream of NOTCH3-stimulated pre-TCR signaling leads to phosphorylation of the transcription factor TAL1, formation of the TAL1:SP1 complex, and activation of cyclin D1 (CCND1) transcription, which stimulates cell division.

NOTCH3 signaling can activate NF-kappaB (NFKB)-mediate transcription either indirectly, through activation of pre-TCR signaling, or directly, through association of NOTCH3 with IKKA. NFKB is constitutively active in T lymphoma cells derived from NOTCH3 transgenic mice.

Transcription of the PLXND1 gene, encoding the semaphorin receptor Plexin D1, is directly stimulated by NOTCH1 and NOTCH3 coactivator complexes. PLXND1 is involved in neuronal migration and cancer cell invasiveness. Expression of FABP7 (BLBP) in radial glia is positively regulated by NOTCH1 and NOTCH3 during neuronal migration.

NOTCH3 gene is frequently amplified in ovarian cancer. NOTCH3 coactivator complex directly stimulates DLGAP5 transcription. DLGAP5 is involved in G2/M transition and is overexpressed in ovarian cancer cells.. Another gene overexpressed in ovarian cancer whose transcription is directly stimulated by NOTCH3 is PBX1. The NOTCH3 coactivator complex directly stimulates WWC1 gene transcription. WWC1 gene encodes protein Kibra, involved in Hippo signaling. NOTCH3-mediated induction of WWC1 positively regulates Hippo signaling and inhibits epithelial-to-mesenchymal transition (EMT) in triple negative breast cancer cells.