**3.1. Caspase dependent pathway**

Caspase-dependent apoptosis is the classic programmed cell death pathway, the capase-8, caspase-9, caspase-12, caspase-7, caspase-3 cascade usually participate in this type of apoptosis pathway, Variety of receptors take part in this type of apoptosis pathway, such as the TNF-alpha receptor, FasL receptor, TLR, Death receptor and so on. Some iron channels may also be involved in apoptosis pathway. The typical iron channel is the calcium channel, Since calcium's concentration in the cytosol plays an important role in the signal transduction regulation and participates in the cell proliferation and cell death, the cell fate can be controlled by the calcium channel opening or closing. In this part, we will discuss the caspase-dependent apoptosis transduction and review the complex signal crosstalk in the cells.

TNF-alpha induced caspase-8-dependent pathway relies on the TNF-alpha receptor and activates the caspase-8 through the death complex, and then the Bcl-2 protein is activated, Bcl-2 family protein activation may induced the mitochondria membrane changed and stimulates the cytochrome c released. Cytochrome c is the proapoptosis signal molecular which can activates the caspase cascade reaction and induced the apoptosis in the end. Some radiation UV or X ray can make mitochondria depolarization and membrane permeabilization, subsequently, the ROS increased; cytochorme c released, and then trigger caspase-9, caspase-3 activation,, In the end, the substracts will be cleavaged by the activation caspases and the fate of cells will be apoptosis; Some pathogen infection induced the apoptosis may be also have the caspase-8 dependent pathway, The alien pathogens can be recognized by FasL receptor and recruit FADD and caspase-8, for example, the intracellular pathogen herpervirus infection can induced the caspase-8 dependent apoptosis. Beside caspase-8 dependent apoptosis, some pathogens can trigger others caspases dependent apoptosis pathway. For example, Mycobacterium tuberculosis can induce programmed cell death on macrophage, and this apoptosis pathway is the caspase-12 dependent. NO and ROS production, stimulated by ER stress, also take part in apoptosis triggered by Mycobacterium tuberculosis; [1] Exclude bacteria, virus also can induce the apoptosis. The latest research found that an alternative Kaposi's sarcoma-associated herpesvirus replication can trigger host cell apoptosis in caspase dependent manner. [2]. Apart

from the bacteria and virus, we found that many researchers' data show that RNA fragments and DNA can also trigger caspase dependent apoptosis, such as RNA fragment produced by mycobacterium tuberculosis which in the early log-phase growth can trigger caspase-8 dependent apoptosis[3]; In vivo, DNA damage can trigger apoptosis through enhancing ROS level and changing the mitochondria membrane permeability; Many proteins or peptides will also make cell apoptosis, amyloid β peptide cytotoxicity can induce the intracellular calcium disturbance, and then the calpain will be activated by imbalanced calcium storage, While the calpain can activate caspase-12 which can located in ER to inactivate the Bcl-Xl, this is a novel caspase-12 dependent apoptosis pathway[4]. This way can be used by the mitochondria to connect with other cell death pathway.

Extrinsic and Intrinsic Apoptosis Signal Pathway Review 7

In this figure, we can clearly know that mitochondrion and nucleus organelles play the pivotal role in this type cell death and these organelles can connect different signals to induce the caspase activation, in this process period, ROS; Cytochorme C release; mitochondrion membrane potential change; Apart the mitochondrion pathway, some ligands can trigger MAPK pathway, such as activate ERK and then activate the caspase

Apoptosis have many mechanisms. It can be triggered by in vitro and in vivo cell ligands, and have different signal transduction pathways. Now, Apoptosis pathways are classified as caspase dependent pathway and caspase-independent pathway. In the above, we describe and conclude the caspase dependent pathway, which is characterized by the involvement of caspase in this type cell death process. In this paragraph, we will deep research the caspase independent apoptosis pathway. We will know that caspase does not participate in this type of process from the literally meaning. Up to now, this type of apoptosis has been founded by many researchers, and the research data give much information to us, this information can help us to understand the apoptosis complex mechanism, beside the mechanisms, the complicated ligands, which can induce this type of cell death, can also be found by many researchers. In the following, we will give some

In the cell, a lot of ligands can induce mitochondria membrane potential change, the mitochondria damage will be the first step of the apoptosis, then ROS production increase, and ROS may the mainly factor to induce caspase independent apoptosis. For example, Denis Martinvalet found that granzyme A can directly induce the ROS increase and caspase independent mitochondria damage. Then the target of granzyme A, ER associated complex (SET complex), will translocated to nuclear and contributed to apoptosis [5]; AIF has been found the major important caspase-indenpendent pro-apoptosis factor, which can release from the mitochondria and translocate in the nuclear to cleavage the DNA, in the end, if the DNA damage have not been repaired by cells, the apoptosis will happen. Recently, many researchers found some compounds which can accompany with AIF production and induce cell death, such as simvastatin, staurosporine, cadmium and so on. These factors triggered caspase-independent PCD and fitted for the organism requirement; Beside AIF triggered caspase-independent PCD, ROS also participate in this type cell death. ROS can mediate poly (ADP-ribose) polymerase-1 (PARP-1) activation, and PARP-1 activation is necessary for AIF release from mitochondria. So ROS also involved in this type of cell death networks.[6].However, ROS participated in the caspase dependent apoptosis pathway also, Consequently, ROS might be the important bridge to connect two types of apoptosis in vivo. ROS mainly come from mitochondria, so mitochondria play important role in apoptosis pathways crosstalk. And the ligands usually trigger complicated reactions, including that AIF nuclear translocation, ROS increase and mitochondrial dysfunctions, these changes can cause to the caspase independent apoptosis pathway. For example, Cyclohexyl analogues of

family which can be confluenced with apoptosis pathway.

detailed contents about caspase independent apoptosis.

**3.2. Caspase independent pathway** 

Above all, we can give the conclusion that pathogens, RNA or DNA, proteins or peptides, some chemical compounds or native compounds can all trigger caspase dependent apoptosis. They may have the different receptors and induce cell death through different caspase as the transducer to make the downstream signals transduction. The host used this way to defense the harmful factors and maintain the healthy physiological state. In the figure 1, we summarized the caspase dependent pathway transduction; we clearly known that the different ligands and receptors involved in this type of apoptosis, this picture will give us the direct impression about this type of apoptosis.

**Figure 1.** Summarize the caspase dependent apoptosis pathway

In this figure, we can clearly know that mitochondrion and nucleus organelles play the pivotal role in this type cell death and these organelles can connect different signals to induce the caspase activation, in this process period, ROS; Cytochorme C release; mitochondrion membrane potential change; Apart the mitochondrion pathway, some ligands can trigger MAPK pathway, such as activate ERK and then activate the caspase family which can be confluenced with apoptosis pathway.
