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Transforming growth factor beta (TGF-β) is a cytokine involved in several cell functions such as proliferation, differentiation and apoptosis. TGF-β is an important molecule and is linked to the development of cancer and tissue fibrosis (Kaminska, 2005). TGFβ was originally detached as one of two elements. In contrast to TGFα, TGFβ possessed powerful growth inhibitory abilities. Consequently, research commenced from this point based on the tumour suppressive role of TGFβ. It was discovered that genetic mutations that led to demise in the TGFβ signalling would eventually lead to carcinogenesis. TGFβ's transforming ability was not studied until almost a decade later, it was demonstrated that once cancer cells had established themselves, TGFβ contributed to their growth, invasion and metastasis (Akhurst, 2001). The diversity of functions of TGFβ has become more apparent and in this essay, I hope to evaluate the role of this molecule.
Structure of TGFβ receptor and TGFβ signalling
TGFβ receptors are composed of an extracellular ligand-binding domain, a transmembrane domain and a cytoplasmic kinase domain. This is similar to the structure of the tysrsine kinase receptor in the sense that both receptors operate through cytoplasmic kinase domains. The TGFβ receptor operates as a heterodimer; type 1 and 2 receptors are bound together as seen in figure 1. The kinase domain phosphorylates serine and theronine residues. When the ligand binds, the type 2 TGFβ receptors subunit is drawn closer to the type one receptor subunit and phosphoylation takes place (Weinberg, 2007). The kinase located on the type 1 receptor consequently becomes activated; this leads to the phosphorylation of SMAD transcription factors 2 and 3 (cytosolic proteins). Once activated the receptor substrate travel to the nucleus and forms a complex with SMAD 4. This complex can bind DNA with high affinity once it has bound DNA-binding cofactors. Each SMAD 4 complex can target a specific set of genes which is decided by cognate binding sequence element combinations in the regulatory regions of target genes (Massague, 2008).
TGFβ is involved in different process,s- discuss.
TGFβ in tumour suppression
The role of TGFβ in tumour suppression was first established by the discovery of the development of tumours in patients that were found to have mutations of the gene TGFBR2. This was as a result of faults in their recombination error repair system. These mutations occur at microsatellite loci throughout the genome. However when certain genes are targeted in which the mutation takes place, a growth advantage is obtained and the mutated cells can rapidly multiply (Markowitz, 1995). TGFβ is only activated under certain conditions such as tissue damage or oncogenic development. Studies on mouse models were carried out with the inactivation of TGFBR2 on mouse epithelium; there was a low subsequent rate of disease occurance which provides evidence regarding the circumstantial applications of TGFβ (Forrester, 2005). Such is the power of the anti-proliferative effect of TGFβ, it was demonstrated that mice deficient of SMAD proteins and therefore disabling the TGFβ pathway had a much faster wound recovery time than wild type mice. The mice with the knockout had a marked improvement in epithelium repair and white blood cell infiltration (Ashcroft, 1999). It was found that the overexpression of active
TGF-1 in Neu-induced mammary tumors resulted in cancers
that were both less proliferative and less apoptotic as well as
more invasive and metastatic than tumors expressing the Neu
transgene alone. This oncogene works in coordination with TGF to progress tumour development.
the tumor evolved into a more metastatic phenotype.
the data implys that, even in advanced cancers,
TGF-_1 may be able to exert tumor-suppressing (antiproliferative)
and tumor-promoting (invasion, motility, and survival)
effects simultaneously(Muraoka, 2003).
This study illustrates that an active TGFβ signal is able to switch on oncogenic development powered by separate signalling stimuli.
Tgfb works as a tumour inhibitor by the method described by Hannon et al., it stimulates an arrest in the G1 phase cell cycle. Cyclin dependent protein kinases (CDK) 4 and 6 are part of the normal development of the G1 phase, these kinases are inhibited by the protein p16ink4. When keratinocytes are treated with TGFB, Another member of this protein family called p15ink4b has been found to be largely expressed. This suggests that the protein p15ink4b has a role to play the arrest of the cell cycle. The gene that encodes this protein is located on chromosome 9 is a common site of chromosomal abnormalities in tumour.
It was discovered through genome-wide transcriptional profiling that the suppression of ids (inhibitors of differentiation) 1,2 and 3 is an element of the cytostatic procedures of TGFB. ID incurs an opposite response to TGFB; SMAD3 in turn activates expression of ATF3. This is a stress response factor which mediates the TGFB stress response pathway (Kang, 2003). Tgfbs cytostatic functions are mediated concurrently by restraining the role of the CDKs and the removal of proliferative inducers. This TGFB response has been also examined in haematopoietic cells signifying that this system is extensively utilised by body cells (Padua, 2009).
As well as the role of TGFB in the regulation of the cell cycle, TGFB can also limit cellular proliferation through its manipulation of apoptotic pathways.
Valderrama-Carvajal et al. studied the signal transduction mechanisms downstream of the TGF-β receptors that lead to apoptosis. It was found that molecules of the TGF-β family regulate apoptosis through expression of the inositol phosphatase SHIP in haematopoietic cells. SHIP is a central regulator of phospholipid metabolism. It was uncovered that the Smad pathway is used in the transcriptional regulation of the SHIP gene. Activin/TGF-β-induced expression of SHIP results in alterations to the pool of phospholipids and also the suppression of both Akt/protein kinase B phosphorylation resulting in cell death. Their study correlates phospholipid metabolism to activin/TGF-β-mediated apoptosis. Their research demonstrates that the TGF-β family serve as potent stimulator of SHIP expression.
Avoidance of tumour suppression systems
It was found that there was a mutational inactivation of core pathway components in cancers such as pancreatic, colorectal, ovarian and ear nose and throat (ENT). However, with other cancers such as prostate, breast and melanomas, a different mechanism failure comes into play??. In these cases, the tumour-suppressive arm of the signalling pathway is removed and so the tumour-suppressive action of TGFB fails to function (Massagué, 2008).
Possibly insert bit about breast cancer model padua.
Breast cancers may accrue defects of cytostatic gene response. It was found that the transcription factor C/EBPB was necessary for the initiation of the cell cycle inhibitor p15INK4b by a FoxO-Smad complex and for the inhibition of c-MYC by a Smad complex in epithelial cells. The results of the study saw half of the patients with a reduction in cytostatic responses (Gomis, 2006). This reduction was proved to be caused by an overexpression of the C/EBPB isoform LIP (liver inhibitory protein) which combines with and inhibits the transcriptionally active isoform LAP. LIP expression may be a useful prognostic marker in breast cancer (Zahnow, 1997).
Patients with breast metastasis had an abnormal ID1 response to TGFB which was induced instead of suppressed. A study by Minn et al. identified a set of genes, one of those being ID1 that implemented breast cancer metastasis to the lung. This evidence was supported by studies on mice that demonstrated that the proteins id1 and id3 were vital for tumour growth once the metastatic cells had reached the lung. In this way, the ID1 gene converts tgfB from a tumour suppressor to a molecule? which is supportive of tumour growth (Massagué, 2008).
Another mechanism of eliminating the tumour suppressive role of tgfb is the deletion of genes responsible for tumour suppression. In certain cancers, there is a mutation on a chromosome which encodes cell cycle inhibitory proteins p15ink4b, ( plus being devoid of p16) these mice demonstrated that the loss of this gene correlated with the development of tumours of an increased size and variety (Krimpenfort, 2007). Earlier studies by Jen et al. indicate that a homozygous deletion of p15 and p16 may be found in cases of glioblastomas rather than a mutation which is thought to be a lesser efficient mechanism of tumour progression.
Cancers types that are capable of shutting down the tumour suppressive arm of the tgfB pathway can benefit from the molecules many tumour promoting aspects (Padua, 2009). In a study carried out by Cui et al., mice underwent log term carcinogenic treatment. TGFβ1 analysis demonstrated biphasic action during multistage skin carcinogenesis, acting initially as a tumour suppressor however afterwards promoting a malignant phenotype.
(There was also a higher incidence of spindle cell carcinomas, which expressed high levels of endogenous TGFβ3, suggesting that TGFβ1 elicits an epithelial-mesenchymal transition in vivo and that TGFβ3 might be involved in maintenance of the spindle cell phenotype. The action of TGFβ1 in enhancing malignant progression may mimic its proposed function in modulating epithelial cell plasticity during embryonic development.)
The epithelial- mesenchymal transition (EMT) is a process which is part of embryonic development and has a role to play in the development of fibrosis and neoplasia (Thiery, 2003). When an EMT takes place in immortalised epithelial cells, this results in the attaining of mesenchymal features. These cells can differentiate into duct like structures and express markers. In these transformed cells, tumours will also arise more easily (Mani, 2008). According to Derynck and Akhurst there is increasing amounts of evidence to suggest that tgfb proteins have the ability to reorganise the cellular differentiation of cells which have already fully differentiated or engage in transdifferentaition. This process is a part of normal embryonic development however occurrence in adults can result in the arising of various disease states.
It was found that the gene HMAGA2 is stimulated by the SMAD pathway during EMT. Non-endogenous HMGA2 caused irreversible EMT branded by severe E-cadherin suppression. A TGF-β signaling pathway was outlined that shows the connection between it and the control of epithelial differentiation via HMGA2 and other major regulators of tumour invasiveness and metastasis (Thuault, 2006).
Ozdamer demonstrated that this dissolution at tight junctions can take place independently of SMAD. The study revealed that Par6 which regulates the polarity of epithelial cell and tight junction assembly interacts with TGFβ receptors and is a substrate of the receptor TβRII. Phosphorylation of Par6 occurs which is needed for TGFβ dependent EMT in mammary gland epithelial cells and the molecular signalling cycle continues culminating in Smurf1 targeting guanosine triphosphatase RhoA for degradation and in doing so losing the tight junctions.
Tumour angiogenesis is essential for the growth and spread of a tumour. Vessels provide the tumour with the nourishment and oxygen needed for progression. A transcriptional complex called hypoxia-inducible factor (HIF)-1 is an important part of oxygen related gene expression. It was found that HIF collaborates with TGFB to induce the action of vascular endothelial growth factor which is a key part of angiogenesis advancement (Sa´ nchez-Elsner, 2001).
Tgfb is also capable of inducing the expression of specific metalloproteases and the decreased expression of tissue inhibitor of metalloproteases in tumour and epithelial cells provide a suitable environment for an increased migratory and invasiveness of angiogenically active endothelial cells (Hagedorn, 2001).
Dickson et al demonstrated that TGF beta 1 is required for yolk sac haematopoiesis and endothelial differentiation. It was found that Mice with a targeted mutation in the TGF beta 1 gene were studied to determine the cause of death. The primary defects were restricted to extraembryonic tissues with the defect in vasculogenesis appearing to affect endothelial differentiation. Defective differentiation resulted in inadequate capillary tube formation and weak vessels with reduced cellular adhesiveness. a reduced erythroid cell number within the yolk sac was the consequence of a defect in haematopoiesis. This study provided evidence that the primary effect of loss of TGFB function is not increased haematopoietic or endothelial cell proliferation, which might have been expected by deletion of a negative growth regulator, but defective haematopoiesis and endothelial differentiation.
TGFB has a potent effect on the immune system and a variety of its characteristics function to counteract its defensive syatems. One such mechanism of tumour evasion is the T-cell−specific blockade of TGF- signalling (Gorelik, 2001). It is though that TGFB acts on cytotoxic T lymphocytes to reduce the expression of five cytolytic gene products. This is caused by the binding of TGFB activated SMAD and ATF1 transcription factor to the promoter regions of the cytolytic gene products which allows control of their expression.
This network of signaling/transcription factors that work sequentially to establish EMT suggests that combinatorial detection of these proteins could serve as a new tool for EMT analysis in cancer patients.