Stem cells are cells which are able to renewing themselves through cell division and can be differentiated into different cell types in the body. These special cells can be found in a microenvironment called stem cell niche and hematopoietic stem cell (HSC) niche is one of the example. The HSC niche gives protection to stem cell from the outside signaling thus to maintain the stem cell characteristic. c-Myc is a protein that function in the HSC niche. It is a intrinsic factor which can induce or repress apoptosis through the c-Myc:Max or Mnt:Max interaction respectively. Experiments have shown that elimination of c-Myc causes decrease in cell proliferation and differentiation. Conversely, over-expression causes the lost of the self-renewal ability and apoptosis. Additionally, c-Myc can control cell growth in cellular level as well. Hence, c-Myc has an essential role in maintain homeostasis inside the niche.
The Stem Cell Niche
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Stem cells are a type of cells which are capable of self-renewal and differentiate into other types of cells in the body. These cells are located in a microenvironment termed stem cell niche. The niche retains stem cells characteristic, regulates stem cells activity and maintains stem cells balance (Morrison & Spradling, 2008). Maintenance of stem cells characteristic is achieved by the interaction between the stem cell niche and stem-cell extracellular matrix-ligand (Wilson et al., 2004). Furthermore, stem cells will undergo differentiation if it leaves the niche since the niche give protection to stem cell which against outside signaling (Thomas & Dattani, 2009).
Hematopoietic stem cell niche
Hematopoietic stem cell niche, which is located in the bone marrow, contains hematopoietic stem cells (HSCs) that reside closely with bone and bone marrow and the cell to cell interaction provides the ability to develop unlimitedly and prevents differentiation to occur (Wilson & Trumpp, 2006). It also has the ability to self-renewal via cell division (Yin & Li, 2006). Further, HSCs are the progenitors of all types of blood cells in human (Smith, 2003). As mentioned above, the niche retains the stem cell characteristic (Morrison & Spradling, 2008); however, the HSCs are able to differentiate into other blood cells when they left the niche (Schofield, 1978). This process allows the maintenance of the homeostatic of stem cells and differentiated cells in the system.
Functions of c-Myc proteins
c-Myc is a member of Myc oncogene family. c-Myc protein is a transcription factors which contains a basic helix-loop-helix leucine zipper domain (bHLH-Zip) (Nilsson, & Cleveland, 2003). c-Myc functions properly if it interacts with a small basic helix-loop-helix leucine zipper protein called Max (Blackwood, & Eisenman, 1991). To activate gene expression, c-myc protein first binds and dimerizes with Max (Nilsson, & Cleveland, 2003). Subsequently the complex binds to a recognition site called E-box CAYGTG motif in the transcription targets gene (Blackwell, Kretzner, Blackwood, Eisenman, & Weintraub, 1990). To inhibit the gene expression, Mad family proteins such as Mad 1 and Mxi 1 and larger protein coined Mnt will dimerize with Max and bind to the same recognition site as mention above (Ayer, Kretzner, & Eisenman, 1993). The interaction between the c-Myc and Max stimulates several intracellular processes such as cell development, differentiation, maintenance of stem cell characteristics and regulates gene expression in the niche (Laurenti, Wilson, & Trumpp, 2009). Thus, c-Myc proteinsââ‚¬â„¢ function depends on the target genes and the E-box that it binds in the genome (Fernandez, Frank, Wang, et al., 2003).
c-Myc signaling pathway and target gene
Apoptosis is an important process for organisms. Cell death may due to serious mutation that the cell can no longer fix. Also, it helps to maintain cell homeostasis in the system. c-Myc has been shown that it can induce apoptosis (Nilsson & Cleveland, 2003). c-Myc induces apoptosis by dimerize with Max first. Then the complex will bind to the E-box in the target gene such as TRRAP along with their related histone acetyl-transferases and ATPase (fig. 1b). Conversely, if a Mad or Mnt proteins dimmerize with Max, c-Myc are no long contact with Max and thus, apoptosis signal is not available (fig 1a). This apoptosis process is an intrinsic pathway that is used to control cell death.
As modified from Reference: Figure 1 from Nilsson & Cleveland, 2003.
Elimination of c-Myc protein leads to decrease in cell proliferation and differentiation
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According to Wilson et al. experiment in 2004, researchers showed that Myc proteins are related to the HSCs self-renewal and differentiation and has the ability to affect the equilibrium between the two. To test whether or not the Myc protein is involved to the equilibrium of the HSCs self-renew and differentiation, the researchers first eliminated the activity of Myc in bone marrow (BM). They crossed c-mycflox/flox mice with the Mx-cre transgenic mice to obtain mutant mycflox/flox mice. The mutant mice is then treated with poly-l-poly (pl-pC) to remove the alleles between loxP sites in the c-mycflox locus in liver, spleen and the BM. Since the HSCs is produced in the BM, the removal of the c-myc in the adult bone marrow results in cytopenia, which is a disease that cause low production of blood cell. Further, most of the c-myc-deficient cells are accumulated in G0 face of the cell cycle. These results state that the removal of c-myc can decrease cells development of a differentiated cell. They also discovered that the c-myc-deficient HSCs fail to differentiate because they are unable to separate from the adhesion molecules such as N-cadherin.
Over-expression of c-Myc protein induces the lost of self-renewal ability and apoptosis
Conversely, researches stimulated the c-myc activity to test if the over-expression of c-myc influences the stem cell self-renewal ability. They infected the wild-type CD45.2+ BM cell with either MYC-IRES-huCD2 or huCD2 control viruses alone and these cells are then combine with the wild-type CD45.1+ BM cells. From this test, they indicated that the over-expression of c-myc causes the lost of long-term self-renewal ability. Afterward, the consequences of c-myc over-expression on HSC survival in vitro was determined by infect the wild-type BM cells with MYC-IRES-huCD2 or huCD2 control viruses again. From here, the data shown that the level of apoptotic cells has no increase in c-myc over-expressing cell (MYC-IRES-huCD2) when compare with the controls (huCD2 alone) and the c-myc over-expressing cells are resistant to death. They therefore concluded that the c-myc over-expression does not lead to apoptosis. Over-expression of c-myc can cause the lost of long-term self renewal ability and inhibit apoptosis, on the other hand, some research shown that over-expression of c-myc can induce apoptosis (Evan et al., 1992). They removed the serum from the cultured medium in c-myc over-expression cells and this can induce apoptosis.
c-Myc has an effect on cell growth in cellular level
The other experiment done by Eilers et al. in 1989 concentrate on the role of c-myc in cellular growth control level. They fused c-myc proteins with the domains of the estradiol receptor. The combination of two proteins is called mycer cells. With the adding of extra estradiol, mycer cells go into S phase in 24 hour. Further study was done by Schmidt in 1999; his research team discovered increase in protein synthesis in mycer cells as well. Additionally, other experiment has been done on rat fibroblasts (Shichiri, Hanson, & Sedivy, 1993). Deletion of single myc allele in rat fibroblast causes 3 hours delay in entering S phase due to myc expression are cut by half. Deletion of both myc alleles causes disappear of the c-myc expression. The time needed for enter S phase has been increased and delay for both G1 and G2 phases of the cell cycle. Decrease in protein synthesis is observed when the c-myc alleles were removed (Schmidt, 1999). These results suggest that c-myc expression has a function on growth control in cellular level.
In conclusion, the interaction between hematopoietic stem cells and the c-myc protein play an essential role on regulating stem cell proliferation and maintain stem cells characteristic. If c-myc is absent in the niche, the stem cell proliferation will decrease since they cannot separate from the adhesion molecule. Conversely, over-expression of c-myc protein will cause the loss of apoptosis and the self-renewal ability of the stem cells.