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together by Ca cations. The mature receptor is available non-canonical ligand or may not require cleavage of
2+
to interact with its ligand, which subsequently stimulates the Notch receptor. Among suggested mechanism of
[1]
through conformational changes a second proteolytic “non-canonical” Notch signaling are interactions of Notch
cleavage by tumor necrosis factor-α converting enzyme with non-CSL transcription factors, such as β-catenin,
[12]
or a disintegrin and metalloprotease (10/17). This in hypoxia-inducible factor-1 α, NF-κB, and estrogen
[4]
[13]
turn results in shedding of the extra-cellular portion receptor α (ERα). Anti-apoptotic activity independent
[14]
of Notch, which through receptor-mediated endocytosis, of canonical functions has been associated with active
propagates signaling events in neighboring cells. The Notch1, which signals via the kinase AKT to prevent
final cleavage occurs within the membrane through the loss of mitochondrial function and consequent nuclear
an associated aspartyl protease known as the γ-secretase damage and requires mitochondrial remodeling proteins
complex composed of presenilin, nicastrin, APH 1 and mitofusins-1 and 2. Notch activity is finely regulated by
[15]
PEN2. Intra-cellular Notch cleaved protein translocates interactions with other key proteins and pathways, among
[5]
to the nucleus where it binds with the transcription factor them p53, ERα, [17,18] the epidermal growth factor B2
[16]
recombining binding protein-Jk or C-promoter-binding (ErbB-2) and the vascular endothelial growth factor
[19]
factor 1/suppressor of hairless/Lag1 (CSL) and, after receptors (VEGFRs), the Wingless (Wnt) [21,22] and
[6]
[20]
displacing co-repressors and recruiting co-activators such Hedgehog signaling pathways. Recent genome-scale
[23]
as p300, histone acetyl transferases, and mastermind-like studies in D. melanogaster have revealed an even more
protein 1 (MAML1), it activates downstream pathways complex network of genes that can affect Notch activity
[24]
[Figure 1]. The “canonical” Notch signaling is known consistent with decades of work showing that the highly
[7]
to activate genes coding for transcriptional factors such conserved Notch pathway is extremely complex, and
as those belonging to the hairy/enhancer of split (Hes1-5), the output of its activation or its inhibition will result in
the hairy-related (Hrt), and the Hes1-5-Hrt with YRPW differentiation, proliferation or increased survival based on
motif (Hey) families involved in inhibiting neuronal the existing cellular context.
differentiation. The “canonical” Notch pathway is a major
[8]
determinant of cell proliferation and survival through the NOTCH SIGNALING PATHWAY IN TUMORS
activation of genes controlling cell cycle progression such
as cyclin D1 and genes belonging to the anti-apoptotic Many reports have been published on the role of the
[9]
pathway nuclear factor kappa-light-chain-enhancer of Notch pathway in the development of the cardiovascular
activated B-cells (NF-κB). [10,11] Notch activation can also system, [25,26] in regulation of stem cells functions such as
[27]
be attained in a “non-canonical” fashion initiated by a survival of cardiac progenitor cells, the differentiation

Figure 1: Schematic representation of the events leading to Notch signaling activation and the steps of this process affected by the oncogenic viruses simian virus
40 and human papillomavirus. Notch precursor is cleaved in the Golgi apparatus by a furin-like convertase and then exposed on the cell membrane. Notch ligands
Delta/Jagged bind Notch extra-cellular subunit. This causes a disintegrin and metalloprotease to clip the extra-cellular portion of Notch transmembrane generating
an intermediate, cleaved by γ-secretase which releases active Notch. Active Notch enters the nucleus, where it causes the dissociation of silencing mediator of
retinoic acid and thyroid hormone receptor corepressor complex from C-promoter-binding factor 1/suppressor of hairless/Lag1, and recruits mastermind-like 1
coactivator complex, resulting in transcription of target genes. Simian virus 40 induces upregulation of the Notch pathway, whereas conflicting reports exist on the
modulation of Notch by human papillomavirus (green arrow indicates up-regulation, red arrow indicates down-regulation or inhibitory binding)

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Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ Issue 1 ¦ January 15, 2016 ¦