Tuesday, 24 August 2010

Oncogenesis: Moving up and down a NOTCH.

Oncogenesis is defined as the progression of cytological, genetic and cellular changes that ultimately lead to uncontrolled proliferation and malignant transformationIn normal tissue, regulatory processes recognise when cells must undergo proliferation, differentiation, repair or death to eliminate renegade cells and prevent the threat of transformation.  Factors that disrupt this regulation contribute to oncogenesis but more than one “hit” is required to actually cause cancer.   

The Notch signalling pathway (see below) is a direct paracrine, cell-to-cell signalling pathway that controls apoptosis, cell cycle, cell proliferation, cell differentiation, neurogenesis and transcription and due to these important regulatory roles, aberrant Notch signalling is considered to assist in cancer progression.  This blog looks at how one aspect of the Notch signalling pathway, the Notch1 receptor, may have an important role in oncogenesis, considering both oncogenic and tumour suppressive perspectives.

The Notch signalling pathway, showing cleavage sites, S1-S3 (red underline),  ligand activation and subsequent translocation of the Notch Intracellular Domain (NICD) to the nucleus where it becomes part of a transcription activation complex.  A closer look at the Notch1 receptor shows the various domains in detail (see abbreviations for further details).

The Notch receptor is an evolutionary conserved transmembrane glycoprotein with an amino-terminal extracellular domain (ECD) and a carboxyl-terminal intracellular domain (ICD).  It is initially synthesised as an inactive precursor which is cleaved by Furin protease in the Golgi apparatus (first cleave known as S1) to produce the Notch ICD (NICD) and Notch ECD (NECD).  These domains then become O-fucosylated by O-fucosyl transferase and glycosylated by Fringe before becoming integrated into the cell membrane.  The transmembrane Notch receptor becomes activated upon the binding of transmembrane ligands from the Delta and Serrate/Jagged (DSL) families.  E3 ligases (Neuralised and Mindbomb) facilitate epsin-dependent endocytosis of the bound ligand to expose the second Notch cleavage site (S2) to metalloproteases ADAM (a disintegrin and metalloptoreinase) 10 & 17 to release NECD.  Cleavage of NECD, in turn, triggers the final cleavage (S3) within the cell membrane by the g-secretase complex (Presenilin-Nicastrin-APH1-PEN2) and releases NICD.  NICD then translocates to the nucleus where it assembles with an ubiquitous DNA-binding protein of the CBF1/RBP-Jk, Su(H) and Lag-1 (CSL) family and other co-activators such as Mastermind-like proteins (MAML) to become a transcription complex which target genes (see table) that ultimately decide the fate of the cell.

NICD target genes for transcription and their role

Humans have four Notch receptors, Notch1, Notch2, Notch3 and Notch4 and five equally conserved canonical Notch DSL ligands and these are Jagged1, Jagged2 and Delta-like 1 (Dll1), Delta-like 3 (Dll3) and Delta-like 4 (Dll4).  Each Notch receptor and DSL ligand combination determines a particular Notch-mediated response; their regulation is extremely important for preventing abnormal cells from transformation and so, as with any biomolecular pathway, aberrant Notch signalling can have extremely compromising oncogenic outcomes but as the following explains, Notch can also result in tumour suppression.

Oncogenic roles of Notch signalling
An illustration of the translocation of the truncated Notch1 in T-ALL
In the haematopoietic system, Notch1 activation is important for T-cell lineage specification and development, demonstrated by Notch1 deletion causing failure of T-cells to develop and increased expression of Notch1 resulting in double positive T-cell’s and inhibition of B-cell development in the bone marrow.  In one form of T-cell acute lymphoblastic leukaemia (T-ALL), a translocation t(7;9)(q34;q34.3) juxtaposes a truncated carboxyl terminal of Notch1 to the T-cell receptor-b (TCRb) promoter/enhancer gene (right).  Subsequent expression of this truncated Notch1, transcribes only for the NICD portion, resulting in a mutant form lacking the heterodimerisation domain and Lin12-Notch repeats (HD-LNR) that function to prevent spontaneous activation in the absence of a ligand-receptor interaction.  The truncated Notch1 protein varies depending on the exact translocation and translation initiation sites; as some remain as transmembrane proteins that require g-secretase processing for activation, whereas others are freely activated within the cytosol. The role of Notch signalling due to the translocation and subsequent over-expression of the NICD component is oncogenic, evidenced by ectopic T-cells developing into aggressive, proliferating monoclonal T-cell tumours expressing N1ICD.

Approximately 40% of human T-ALLs contain mutations within exons 26 and 27, which encode for the HD region and this demonstrates its importance in stabilising Notch signalling.  Further Notch1 mutations, other than within the HD region, have been identified in T-ALL, including the PEST region, PEST and HD combined, juxtamembrane and transactivation domains, each with a consequent oncogenic outcome.  Additional evidence for an oncogenic role of Notch1 in T-ALL is demonstrated by over-expression of c-Myc (only) proving insufficient in causing T-ALL, yet an additional Notch1 mutation (induced by viral insertions) targeting c-Myc subsequently induced tumour progression.

Mutations, however, are not the sole means for Notch1 contribution to oncogenesis.   Wild type Notch1 signalling may be a downstream effector of oncogenic Ras as increased Notch1 signalling, simply through Ras up-regulating the Notch ligand Delta-1, provided a complimentary environment for sustaining mammary tumours.  Another non-mutation-derived oncogenicin which an increased activity of the pathway through increased expression of Notch ligands and receptors, was induced by a hypoxic environment.  Hypoxia is a shared attribute of solid tumours, with many over-expressing Hypoxia inducible factor 1a (HIF-1a), known to initiate further invasion, angiogenesis and distant metastasis.    The research suggested the effect of hypoxia on Notch signalling was due to the accumulation of HIFs that synergistically activated transcription of both HES1 and HEY1 with the Notch coactivator MAML1 and that Notch activation correlated with hypoxia-mediated breast cancer cell invasion and metastasis.  A similar study of adenocarcinomas of the lung showed that, under hypoxia, inhibition of Notch1 signalling induces apoptosis of the tumour cells and that Notch1 activation maintains an oncogenic role by activating Akt-1 through repression of phosphatase and tensin (PTEN) homologue and induction of insulin-like growth factor-1 receptor (IGF-1R) where IGF-1R functions to protect the tumour cells from g-secretase inhibitor (GSI) toxicity, which would normally induce apoptosis.  Earlier research also compliments these findings as they found a dependency of malignant mesothelioma cells, under hypoxia, for increased Notch1 activity to increase the prosurvival phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) signalling pathway and maintain their tumourigenic state. 

Tumour suppressive role of Notch signalling
NOTCH1 plays an important tumour suppressive function in the context of epithelial tumours, demonstrated widely using mouse skin models.   Loss of Notch1 has the same outcome as loss of p21WAF/Cip1 (cell cycle inhibitor at S phase) on both stem cell populations of keratinocytes and ras- and chemically-induced carcinogenesis of the skin.  In the basal cells of the skin Notch1 signalling halts the cell cycle via increasing p21WAF/Cip1 expression, which promotes terminal differentiation and Notch1-/- mice demonstrated spontaneous skin lesions similar to basal cell carcinomas (BCCs).  Interestingly, BCCs in humans, which are commonly linked to aberrant Sonic-Hedgehog (Shh) signalling, showed reduced Notch1 expression associated with increased and sustained Gli2 expression, which is a downstream target of the Shh signalling pathway.  A tumour suppressive role for Notch1 has been demonstrated in mouse skin as Notch1 ablation resulted in epidermal hyperplasia followed by skin tumours and facilitated chemical-induced skin carcinogenesis, also by means of sustained Gli2 expression.  Also identified is inactivation of Notch1 reduced the beta-catenin/Wnt (Wingless/Integration) signalling pathway, thus preventing cells from undergoing differentiation.

Notch1 activation resulted in a significant in vitro and in vivo growth inhibition of hepatocellular carcinoma (HCC) cell line SMMC7721, through decreased expression of cyclin A1, cyclin D1, cyclin E, CDK2, decreased phosphorylation of Rb and increased expression of p21 (cell cycle arrest) together with p53 up-regulation and Bcl-2 down-regulation (apoptosis) (see below).

The tumour suppressive effect of increased Notch1 activity on cell cycle and apoptosis in Human Hepatocellular Carcinoma, demonstrating a G0/G1 cell cycle arrest and increased apoptosis, concluded as Notch1 activation induced.

Notch1 is also expressed in low levels in HCC and this correlated with high levels of beta-catenin, suggesting that up-regulation of Notch1 signalling in this context maintains tumour suppression.  Comparatively, however, some studies concluded that Notch1 in fact has an oncogenic role in HCC with HCC cells, when compared to normal adjacent hepatocytes, showing an up-regulation of cytoplasmic Notch1; sometimes together with increased expression of HES-1 gene also.  The oncogenic role of Notch1 in HCC was demonstrated by exposing the tumour cells to a Notch1 inhibitor (curcumin), which resulted in a dose-dependent N1ICD reduction, HCC cell growth inhibition and apoptosis, including a 40% reduction in tumour growth in vivo.  Presently, the determining factors that dictate which role Notch1 undertakes in HCC is still uncertain.

Varied oncogenic and tumour suppressive roles of Notch Signalling
In cervical cancer, Notch1 signalling is known to have both oncogenic and tumour suppressive qualities.
"Double edged sword" roles of Notch1 in cervical cancer
In cases of squamous metaplasia of cervical columnar epithelium in early Human Papilloma Virus (HPV) induced cervical intraepithelial neoplasia (CIN) I-III or well differentiated superficial cervical carcinomas, Notch1 expression is increased, leading to suppression of c-Fos protein expression and induction of Fra-1. The result is a negative regulation of HPV dependent transcription, activation of p53 and subsequent p21 activation that, in turn, initiates differentiation and repression of both Wnt and Shh signalling pathways that ultimately lead to tumour suppression. In low grade CIN, HPV-E6 and HPV-E7 genes demonstrate low expression, however, in high-grade malignancies, expression is high and to maintain the transformed malignant phenotype, this is sustained by down-regulating Notch1.  

The oncogenic activity of HPV-E6 suppresses p53 by targeting it for ubiquitination and degradation whereas HPV-E7 inhibits p21 and functionally inactivates p105-Rb, thus providing the virus with complimentary alterations that assist cell transformation and tumour progression (above).  Another oncogenic role of Notch1 in cervical cancers is playing part to two pro-oncogenic effector mechanisms, namely PI3K/Akt pathway activation and up-regulation of c-Myc that correlate with the dose-dependent effects of Notch1 on papillomavirus oncogenes.

Cross talk between signalling pathways.
Notch signalling also plays a role in oncogenesis by means of cross talking with other signal transducing pathways. The example above shows how increased Notch1 activity in early HPV-induced lesions repress both Wnt and Shh pathways and how late-stage cervical cancer leads to ubiquitination of p53 as a result of down-regulated Notch1 signalling, so can be considered as an indirect control of these pathways.  Another indirect method of p53 suppression is shown in a form of T-ALL, in which up-regulated Notch1 activity decreases the activity of p14(ARF) which is a negative regulator of MDM2 (an E3 ubiquitin ligase), subsequently leading to  increased activity of MDM2 which targets p53 for degradation.  A third example shows how deletion of FBXW7/SEL-10 (F-box protein Fbxw7 that mediates the ubiquitination of cell cycle regulator proteins), increases Notch1 activity in mouse embryonic fibroblasts, causing tumour growth suppression by up-regulation of p53.

Opposing the tumour suppressive crosstalk of Notch and Wnt signalling pathways seen in early HPV lesions, is the oncogenic role in human intestinal tumours, where the majority show loss of the adenomatous polyposis coli (APC) gene, a key negative regulator of Wnt pathway.  Initial research into murine adenomas showed that Notch activation in mice heterozygous for loss-of-function APC gene resulted in a significant increase in number of adenomas compared to the heterozygote littermates lacking Notch activation. The crosstalk between Notch and Wnt signalling was evidenced by the majority of adenoma cells expressing active proliferation together with activated Notch transgene and the nuclear localisation of b-catenin.  When immunohistochemistry demonstrated that human adenomas expressed higher levels of Notch1 and Notch targets Hes1 and Hey1 than adenocarcinomas, it was concluded that increased Notch signalling may contribute to the transformation of benign adenomas to colorectal cancer.

In summary, from the research studied in this essay, Notch1 has shown oncogenic roles through over-expression of NICD (T-ALL), increased wild–type activity (breast cancer) and a down-regulation of Notch1 (high-grade cervical cancer).  In these cases, Notch1 alone may not be the sole cause of oncogenesis, but rather a contributor along with other oncogenic influences and, evidently, oncogenic Notch1 is not necessarily a mutant gene or protein, as simple up-regulation or over stimulation from upregulated ligands can be responsible in wild-type cases.  Tumour suppressive roles of Notch1 activation have also been demonstrated with its absence or dysregulation resulting in hepatocellular carcinoma, BCCs and BCC-like lesions, although contradicting ideas exist with regards to HCC, possibly indicating an unknown cross talk with other signalling pathways or some undetermined link to specific HCC cancer cells.  Notch activity outcome is also shown to be context-specific such as the increased activity seen in breast cancer cell invasion and metastasis in response to increased HIFs, as well as the varied stages of HPV-induced lesions in cervical cancer.  An important aspect of the role of Notch is how interactions with other signal transducing pathways contribute to oncogenesis.  Again, there is no strict rule for Notch1 activity outcome with a particular pathway, as shown with Wnt cross talk, where in early HPV lesions, an increase in Notch1 activity results in tumour suppression, but in human intestinal tumours this is oncogenic.  Similarly, Notch1 crosstalk with the p53 pathway also showed varied outcomes, as increased Notch1 activity resulted in decreased p53 in T-ALL and mouse embryonic fibroblast tumours and decreased Notch1 activity resulted in decreased p53 activity in late HPV lesions.

Notch1 is only a single aspect of a much larger scaled complex signalling pathway that makes up Notch signalling, with three other receptors and at least five different ligands.  The full extent of the Notch signalling pathway and its role in oncogenesis is beyond the scope of this blog, however, what can be deduced from the insight into one part of it is that Notch1 signalling shows varied roles in oncogenesis where the signal outcome proves dependent on cell-type, context and which other signal transducing pathway it interacts with as these may ultimately be the definitive causative factor of oncogenesis.  Also, when aberrant Notch1 signalling occurs, other Notch receptors are unable to substitute themselves for the defective one to complete normal signal transduction, therefore each Notch receptor must have a specified allocated, possibly contrasting role from the next.  Despite so many routes for aberrant Notch1 signalling, many could prove to be good prognostic markers, because by understanding them, targets can be identified for possible anti-neoplastic treatments, as it is crucial when considering which malignancies would respond to Notch-antagonising or Notch-inducing therapies. 

ADAM, a disintegrin and metalloptoreinase
ANK, The ankyrin repeat region of intracellular Notch,
APC, adenomatous polyposis coli,
BCC, Basal Cell Carcinoma.
Ca, Calcium,
CIN, Cervical Intraepithelial Neoplasia
CIR, CBF1 Interacting co-Repressor,
CSL, The nuclear transcription factor bound by activated Notch, also known as RBP-Jκ,
recombination-signal-sequence-binding protein for Jκ genes, or CBF1 in mammals, Suppressor
of Hairless in D. melanogaster, and LAG-1 in C. elegans.
CtBP, a co-repressor that recruits HDACs,
DSL, Canonical Notch ligand of the Delta, Serrate, or Lag-2 family.
ECD, extracellular domain
EGF, Epidermal Growth Factor, EGF-like domains are present in the extracellular domain of
Notch and ligands
GSI, g-secretase inhibitor.  Gamma secretase is the multisubunit membrane protease that cleaves Notch receptors at site S3 during receptor activation,
HAT, Histone acetyl transferase,
HCC, hepatocellular carcinoma,
HD, Heterodimerisation domain. This domain immediately precedes the membrane, and contains the furin (S1) and metalloprotease (S2) cleavage sites.  This folds with LNR to form a molecular lock to prevent spontaneous activation of the receptor in absence of ligand-receptor interaction.
HDAC, Histone deacetylases co-repressors,
HES-1, Human Enhancer-of-split homolog 1, a Notch target gene containing sequence-paired
sites in its proximal promoter region.
HIF, Hypoxia Inducible Factors,
HPV, Human Papilloma Virus.
ICD, intracellular domain
IGF-1R, insulin-like growth factor-1 receptor,
LNR, Lin12-Notch repeats. Each repeat is about 35–40 residues long, and contains three disulfide bonds. This folds with HD to form a molecular lock to prevent spontaneous activation of the receptor in absence of ligand-receptor interaction.
MAM, Mastermind, a specialized transcriptional co-activator that binds to ICN/CSL
complexes. The three Mastermind-like proteins in mammals are designated MAML1–3.
MIB, Mindbomb,
mTOR, mammalian target of rapamycin,
N1ICD, Notch1 intracellular domain
NECD, Notch extracellular domain
NEUR, Neuralised,
NICD, Notch intracellular domain
NF-kB, Nuclear Factor kappa-light-chain-enhancer of activated B cells
NRR, Notch Negative regulatory region, which includes the three Lin12-Notch repeats (LNRs)
and the heterodimerisation domain.
PEST, Proline (P), glutamic acid (E), serine (S) and threonine (T) rich
PI3K, prosurvival phosphatidylinositol 3-kinase
PTEN, phosphatase & tensin homologue
RAM, RBP-Jκ associated molecule, the region of intracellular Notch immediately C-terminal
to the transmembrane segment.
Rb, Retinoblastoma protein,
SHARP, (or MINT/SPEN), recruits CtBP
Shh, Sonic Hedgehog pathway.
SKIP, Ski-interacting protein
SMTR, (or NcoR), a co-repressor that recruits CtBP,
T-ALL, T-cell Acute Lymphoblastic Leukaemia
TCRb, T-cell receptor-b promoter/enhancer
TM, transmembrane.
TACE, TNF-alpha converting enzyme, a metalloprotease implicated in Notch cleavage at S2
Wnt, coined from the combination of Wingless (Wnt) and Integration (Int) names.

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