AbstractTafazzi.0n (TAZ) protein is a coactivator of transcription which is utilized as an effector for the signaling of the Hippo pathway.  It is a gene that codes for a protein. The protein TAZ has many roles in the human body; recent studies have shown that it also collaborates with stem cells.  TAZ can cause two distinct events to happen with a stem cell depending on where it is located inside of the cell (Cordenonsi et al., 2011).

  If the protein TAZ is located inside of the nucleus, the stem cell will differentiate into a specialized cell, and if the TAZ is located inside of the cell’s cytoplasm, the cell will duplicate and create more undifferentiated stem cells.  The amount of the TAZ protein is also relevant, particularly in cancer stem cells (CSCs) (Lei et al 2008).IntroductionStem cells are cells that might be found in every human body; they have the potential to develop into many different kinds of cells, and this is called differentiation.  Stem cells differ from other cells types based on two main characteristics: they are unspecialized cells that have the ability of renewing themselves via cell division and, under certain conditions, may be induced to become tissue or organ specific cells (Stem Cell Basics) (Lei et al 2008).  There are two different kinds of stem cells: embryonic stem cells and “somatic” stem cells.

  Embryonic stem cells are considered pluripotent, meaning that they can differentiate into all of the cell types that make up the body.  Somatic stem cells are considered multipotent, meaning that they can differentiate into more than one cell type but are limited and are not as versatile as embryonic stem cells.  Although human embryonic stem cells may be better for research, it is controversial to use them; so many researchers have started using mouse and other mammal embryonic stem cells for their research (McGee et al., 2001).Stem cell research has been a point of controversy both in the past and currently, although it is becoming more accepted as new methods of collecting stem cells emerge.

  Many scientists believe that stem cell research holds a lot of potential importance for the future, hence the increase in research in that area (McGee et al., 2001).  One important type of stem cell research involves testing the effects of different proteins on stem cells and determining which ones have a significant effect.  One of these proteins is the protein Tafazzin (TAZ); scientists have discovered that, depending on where it is located, TAZ may cause the cells to replicate or differentiate into specialized cells.  It is crucial to have a full understanding of the importance of TAZ, how TAZ works in stem cells, and the future of TAZ protein as well as having an association with Hippo signaling pathway and cancer or tumor cells (McGee et al., 2001).Protein is encrypted by a TAZ gene and is found in the nucleus and is known as Tafazzin (TAZ).

   Another important facet of TAZ relates to the modular protein domain (WW domain) which allows creating interference with protein ligands.  The WW is found in signaling structural proteins and allows certain proteins to signal up to four times (Chen et al., 2010).  The protein TAZ which is the WW domain contains a transcriptional coactivator which modifies mesenchymal distinction and development of various organs of the body.  TAZ is not used only for signaling but also for inducing cellular behaviors such as alteration of tumorigenic growth proliferation (Murakami et al., 2005). TAZ is an essential protein for the duration of cell differentiation and organ expansion, and if the TAZ protein is missing or the signal does not take place, the organs would have a mutation.  The TAZ protein expresses itself exceedingly in skeletal and cardiac muscles and is greatly involved in metabolism and signaling between stem cells (Cordenonsi et al.

, 2011).  Figure 1: The diagram displays elements that are downstream of the anticipated Hippo pathway.  YAP/TAZ-TEAD are transcription features that are stimulated and the DYRK-DREAM (in peach color) represents inactivation during the Hippo signaling loss. The figure also indicates the association that YAP and TAZ have with the Hippo signaling pathway (Kim et al., 2013).According to Figure 1, products resulting from transcription are involved in the regulation procedure of a number of proteins which are associated with the proliferation and migration of cells.  As presented in Figure 1, YAP and TAZ partake in controlling the proliferation melanocytes that are cultured.  The particular components of the development medium and cultured substrates provide the proliferation signaling.

  Signaling due to the extracellular mechanosensory which ascends from the shape of a cell and polarity in addition to various signaling extracellular molecules, and the regulation of the Hippo pathway is upstream.  The loss of the Hippo pathway signaling creates uncontrolled cell growth (polyploidy) and tumor cell growth (polyploidy). The transcriptional activator is maintained by the signaling pathway, and when it is active and the formation of the YAP and TAZ is phosphorylated in the cytoplasm, inhibition of the proliferation of cells occurs (Kim et al., 2013).TAZ protein is closely associated to the Yes-associated protein (YAP) which is a critical mediator.  They both are WW domain in which mediating interaction among proteins occurs.

The Hippo tumor suppressor pathway inhibits both YAP and TAZ transcriptional coactivators and has downstream objectives. YAP functions by regulating transcriptional activity preceding the induction of its cell-death. TAZ and YAP play a critical role during tumor and cancer suppression. The active form of TAZ is found only in the basal cells and is important for maintaining basal cells throughout homeostasis (Kim et al., 2013).The defect in the TAZ protein causes numerous disorders and Barth syndrome (BTHS) which is an X-linked disorder is well-recognized.

  The BTHS is cause by the remodeling of cardolipin and is also known as single-gene disorder. In order to test the effect of the defect TAZ, 42 patients with BTHS disorder were examined by comparing muscle strength echocardiographs and by examining physical and mental exercises. According to the result from the experiment conducted by Thompson et al., almost all patients showed significant reduction in the functional exercise capability during the defection of TAZ protein.

The study leads to the establishment of targets for therapeutic monitoring and authenticated opportunities for medical assessment. Furthermore, it provided perception into BTHS (Thompson et al., 2016).When talking about TAZ, YAP, and stem cells, it is essential to have a good understanding of the signaling pathway known as Hippo signaling, since it plays a critical role in sending signals in between cells. Hippo signaling which is a well-maintained evolutionarily pathway, synchronizes the proliferation of cells, apoptosis and the self-renewal of stem cells (Hu et al, 2013).

   The Hippo signaling has a crucial benefit when it comes to organ size regulation and tumorigenesis which is a physiological and pathological process. Furthermore, in the regulation of the signaling pathway, YAP and TAZ are fundamental Hippo signaling pathway and transcriptional co-activators. All there (YAP, TAZ, and Hippo signaling pathway are involved in the early development of embryos (Zhao et al., 2010). Results Figure 2: The figure shows how TAZ helps in differentiation and prediction of tumor cells.  Also it displays the response of the tumor cells at a high and low TAZ level. The effect of the Hippo signaling being on or off in association with the TAZ is also presented.According to Figure 1, TAZ and YAP activities are associated closely.

   When the Hippo signaling is on, the TAZ level is low, but when the Hippo signaling is off, there is a high level of TAZ.  The high level of TAZ due to the Hippo signaling being off presents the traits related to cancer stem cells.  The turning off of the Hippo signaling is due to the loss of cell polarity initiating the absence of the inducing factor.  Figure 1 clearly presents that the TAZ and YAP have activities that are associated and work hand in hand with stem cell and are a clinically applicable tool in predicting disease (Cordenonsi et al.

, 2011).  Based on the figure above when the Hippo signaling pathway is off, it directed a high level of TAZ growth causing a trait that is most associated with cancer stem cells. It is essential to have the Hippo signaling pathway which would lead to the production of enough TAZ protein in order to have a control (Kim et al., 2013).  Figure 3:  The figure above show the role of YAP/TAZ and the images were revealed using fluorescence. The low magnification shows the expression of the embryo.

FP represents fluorescent protein; cTNT is the chicken troponin T. The investigation was mainly done to examine the association of YAP/TAZ with Hippo signaling pathway. In relation to Figure 3, the zebrafish embryo during the premature development required the YAP protein.  When the YAP was reduced, the apoptosis increased, proliferation of cells was decreased, the standard pattern and somitogenesis (somatic formation) were disturbed, and the development of cardiogenesis (embryonic heart development) and hematopoiesis were delayed.  The study of zebrafish during the embryonic development period presented a better understanding of the function of YAP in the Hippo signaling pathway.

  Furthermore, the deficiency of TAZ caused bone formation of the zebrafish embryos to be defective (Hu et al., 2013).  The investigation also indicated the ongoing investigation YAP/TAZ-Tead and the consequence that the signals they send have on the Hippo pathway regulator. TAZ protein might be the future’s cancer cure solution through some signal manipulations (Miesfeld et al., 2014).Having a complete understating of how the protein TAZ works in stem cell is critical in order to comprehend its role in the inner ecosystem.

  The location of the TAZ protein determines the differentiation effects on stems cells.  TAZ may be found in either the nucleus or in the cytoplasm of a stem cell (Cordenonsi et al., 2011).  When TAZ is located in the nucleus, it prompts the cell to differentiate into specialized cell types.  However, if the protein TAZ is found in the cytoplasm, it causes the stem cell to divide and create more of itself in an undifferentiated state.

  There has also been some research focusing on the differences when different levels of TAZ are present.  Some scientists have noticed changes and differences in stem cells and CSCs when higher or lower amounts of the protein are present. According to research presented in both Jögi and Cordenonsi’s articles, different amounts of the TAZ protein play a role, particularly in cancer stem cells (CSCs).  If large amounts of TAZ are present, the CSC may have a higher chance of metastasizing where if the amounts are lower, then the chances decrease.  The presence of the TAZ protein in any cell may be too low for it to impact the cell; only a certain amount of TAZ protein may alter what a cell does regardless of where it is located within the cell (Jögi, et al., 2012). The level of TAZ protein produced is essentially controlled through the Hippo signaling.

  It was also noticed that in poorly differentiated tumors, the CSCs have elevated levels of the protein TAZ. (Cordenonsi et al., 2011).  Scientists haven’t been able to pinpoint the exact function of the TAZ protein, although it has been noticed that it may act as a transcriptional coactivator when overexpressed.  TAZ and YAP contain a WW domain that binds to Pro-Pro-X-Tyr (where X is any amino acid) patterns.  A number of transcription factors include the Pro-Pro-X-Tyr pattern within their activation domains, meaning that the interaction of TAZ with these and other transcription factors may be involved in mediating their transcriptional effects.

  Although an exact function of the TAZ protein within stem cells may not be reached, researcher, recognize how it interacts with other proteins and how it may affect cells based on where and in what amounts it is present (Hong et al., 2005). As discussed above, TAZ and YAP interact with numerous transcription factors.  These TAZ and YAP interactions have been implicated in a variety of biological processes.

  TAZ and YAP are often coexpressed in embryonic tissues, and each has their own set of DNA-binding proteins that they are associated with. This suggests that TAZ and YAP may fulfill their own separate roles, but overlap in various organs in vivo.  In addition, TAZ and YAP also act as transcriptional repressors in some cases, meaning that their effects on specific genes likely depend on their association with DNA-binding proteins, coactivators, and corepressors (Murakami et al., 2005).One of the most important proteins found in the cell is TAZ. The protein plays a critical role in the human body during development and in the cardiac and skeletal muscles.

  Gene expression is mainly performed by the TAZ protein since it contains an important coactivator that allows for the binding of DNAs (Murakami et al., 2005).  In addition to its standard tissue developmental role, the critical roles that the TAZ provides are cell proliferation, cell distinctiveness, apoptosis, movement, incursion, and epithelial-mesenchymal transition (EMT).  The essential characteristic of stem cells that provides distinction of human cancers among various other cells through stem cell regulatory system also makes TAZ an essential protein in living organisms (Olson, 2005). Scientists believe that the TAZ may provide many solutions to mental health problems that are faced daily, since they believe that the alteration of the signal that is sent by the TAZ molecule could provide a long term cancer cell curing solution ((Jögi et al., 2017).   Another crucial aspect of TAZ is its presence in cancer stem cells (CSCs).

  Scientists have noticed that tumors most often form in tissues and organs that undergo constant regeneration.  It is hypothesized that tumors form and progress due to cancer stem cells because stem cells are normally responsible for those areas that undergo constant regeneration (Zhao et al., 2010).  The research by Cordenons, showed that the activity of TAZ is required to sustain self-renewal and tumor-initiation capacities in breast CSCs.  He also shows that TAZ protein levels are actively elevated in prospective CSCs and in poorly differentiated human tumors and have prognostic value.  In his conclusion, he notes that his collected data provides evidence that cell populations with CSC properties express higher levels of the TAZ protein, meaning that the level of the TAZ protein in a stem cell may cause the cell to become cancerous.  Knowing how the TAZ protein works in CSCs may be crucial to further research on cancerous tumors (Cordenonsi et al.

, 2011).The future of TAZ protein seems to be unique and hopeful among scientists for discovering many disease cures, for detecting it early and alerting TAZ to prevent the disease. The protein TAZ could become a useful tool for scientists because of its effect on stem cells.  TAZ could be used to create more undifferentiated stem cells by adding the TAZ into the cytoplasm of existing stem cells, creating more undifferentiated stem cells to work with for experimental purposes (Miesfeld et al., 2005).  The protein TAZ could potentially also be used to control when and how a stem cell differentiates into a certain type of cell.  Knowing how TAZ works and how it can affect stem cells may lead to an important use of the protein for research.

        The TAZ protein has already been in use for curing illness.  An example could be seen from an article titled “The Hippo Transducer TAZ Confers Cancer Stem Cell-Related Traits on Breast Cancer Cells”.  The experiment described in this article studies TAZ protein levels in relation to cancer stem cells (CSCs); TAZ protein levels were higher in CSCs and in poorly differentiated tumors.  They also found that high expressions of TAZ and YAP proteins in a CSC have a higher chance of metastasizing which reduced survival of the cancerous cells, and those with lower TAZ and YAP were less likely to develop metastasis.  Not only is the presence of the protein TAZ important, but these articles illustrates that the level of the TAZ protein in stem cells is also a significant end product in the human cells (Cordenonsi et al., 2011).

Another example of the protein TAZ being used in research comes from Murakami’s article and research on its effect as a coactivator for TBX5, a transcription factor implicated in Holt-Oram syndrome.  Holt-Oram syndrome is characterized by congenital defects in the heart and upper extremities.  The transcription factor TBX5 plays a crucial role in cardiac and limb development, and various mutations in the TBX5 gene have been found in patients with Holt-Oram syndrome.  In this study, they identified a WW domain containing TAZ as a potent TBX5 coactivator.  The protein TAZ directly associates with TBX5 and stimulates TBX5-dependent promoters.  The mutants of TBX5 that were identified in patients with Holt-Oram syndrome were markedly impaired in their ability to associate with and be stimulated by TAZ.

  These findings show key roles for TAZ in the control of TBX5- dependent transcription and therefore suggest the connection of these coactivators in cardiac and limb development (Murakami et al., 2005). ConclusionThe protein TAZ is important in many ways throughout the human body, and the interaction it has with stem cells, YAP and the Hippo signaling path way are some of the thought-provoking concepts to be considered.  TAZ plays important roles in cell proliferation, cell distinctiveness, apoptosis and more.  It also partakes in an essential role in stem cells, depending on where it is located (Cordenonsi et al.

, 2011).  TAZ may either have the cell differentiate into a specialized cell or cause the cell to self-renew.  This development in the research of protein TAZ may lead to the possible use of the protein for research with stem cells.  Knowing how to use and manipulate stem cells with the TAZ protein could lead to more knowledge and research done on stem cells (Kaan et al., 2017).  In order to study the differentiation of stem cells with the use of the TAZ, numerous experiments were performed on mice because they are similar to humans, have a shorter life span, and are able to reproduce quickly (Hong et al., 2005).

The experiment showed that the TAZ could be an essential tool of the future by providing stimulation of renewable stem cells which could be used as application of regenerative medicine. The technique could allow the generation of therapy that is most suitable for replacing the initial cell.  The TAZ protein along with the YAP protein were shown to work within CSC and, based on their levels, may have the CSC develop metastasis if levels are too high or if they are too lower may not cause the CSC to develop metastasis.  This experiment is a good example of how the TAZ protein may be used in a research setting to better understand its effect on stem cells.

  The experiment shown in Figure 2 was done on one of the important model organism disruption of YAP/TAZ activity and caused a failure of midline migration for cardiac progenitor cells resulting in significant cardia bifida (Finch-Edmondson et al., 2015).The Hippo pathway signaling is interrelated with the YAP/TAZ. They both are used during the study of the zebrafish development. Even though TAZ protein seems to be one of the most important proteins found in the cell and works closely during the stem cell signaling, it seems as if the TAZ protein needs other protein like the YAP protein and Hippo signaling pathway in order to complete some processes (Hong et al.

, 2005).  The zebrafish experiment was closely monitored while manipulating YAP/TAZ activity.  The restriction of YAP and TAZ which is a transcriptional co-activator interaction with DNA binding Tead the epithelia eye cell loses.  Also this experiment allowed the scientist to use another model organism (Drosophila) in order to investigate the regulation of Hippo signaling.  The Hippo signaling was investigated using YAP/TAZ-Tead as well (Miesfeld et al., 2014).In conclusion, TAZ is a protein that works in collaboration with YAP and Hippo signaling pathway in addition to working tirelessly in order to regulate and maintain homeostasis, it engages in fighting cancer and tumor cells.

Even though TAZ is an essential protein in the inner ecosystem of individuals, it requires YAP (a transcriptional coactivator and mediator protein) and Hippo signaling pathway (pathway used to regulate homeostasis and controls the organ size). With respect to, Figure 1, the loss of the Hippocampus signaling pathway lead to a low level of TAZ and YAP and leads to the uncontrolled production of organ cells and cancer/tumor cells ((Kim et al., 2013).   Consistent with Figure 2, it presents a clear depiction regarding what happens once the Hippo signaling pathway in the cell is turned on or off.  When it is on the TAZ level is low and when it is off the TAZ level is high (Cordenonsi et al.

, 2011).  Lastly in Figure 3, the YAP/TAZ-Tead experiment on the zebrafish and Drosophila showed the underlying force of YAP/TAZ-Tead importance in the innovative insights of the regulation of the Hippo pathway for vertebrates ((Finch-Edmondson et al, 2015).  The TAZ has an incredible work scheme with an important role in combination with a future that could change the face of the medical world in association with tumor and cancer cells. 


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