The cell cycle is a highly ordered process that results in the duplication and divides into two daughter cells. Cancer cells acquire unlimited replication potential and continue to divide without progressing into immobility and senescence (Hayflick 1997; Sherr 2000;
Tyson & Novak 2001). And so to understand cancer we require to know what is cell proliferation and how is it regulated? The eukaryotic cell cycle is divided into two phases, interphase and mitosis. Interphase includes：G1 (gap phase 1), S (DNA synthesis), and G2 (gap phase 2).
During G1 phase, the cell is subject to stimulation by extracellular mitogens and growth factors and integrates growth preparation of the chromosomes for replication. S phase is defined as the synthesis of DNA and duplication of the centrosome. G2 phase is a process after S phase that the cell prepares for division. In mitosis (M) phase, the duplicated chromosomes segregate and cell division (Sherr 2000).
Finally, there is a fifth state, G0 (also known as quiescence/temporarily or permanently out of cycle) into which the cell may reversibly exit from G1, if it is response to growth or mitotic signals (Lundberg &
Weinberg 1999; Israels & Israels 2000; Park & Koff 2001; Murray 2004).
2. Cell cycle checkpoint
Cell cycle events are regulated by a network of many molecular signals at a number of positions within the cell cycle known as checkpoints. Checkpoint as a mechanism for monitoring the integrity of DNA are strategically placed at the G1-S and at the G2-M phase, the events in each phase are complete before moving to the next, that cells with DNA damage do not replicate (Israels & Israels 2000; Park & Koff 2001). Progression through each phase of the cell cycle is regulatory via many molecules, including cyclins, cyclin-dependent kinases (CDKs), and cyclin-dependent kinase inhibitors (CKIs). In general, cell cycle transitions are controlled by CDK family of serine/threonine kinases.
These holoenzymes contain both regulatory (cyclin) and catalytic (CDK) subunits that the activity of each of these kinases is dependent on its association with cyclin. Different cyclin/CDK complexes are expressed only in the appropriate phase of the cell cycle, phosphorylate specific protein substrates to move the cell through the cycle, and controlled via degradation by ubiquitin-mediated proteolysis (Sherr & Roberts 1999).
The cycle begins in G1, a critical time where extracellular signals both positive and negative, by D cyclins (D1, D2, and D3) associate with CDK4 and CDK6 (Sherr & Roberts 1999). Formation of the cyclin/CDK complexes results in phosphorylation and activation of the CDKs. The activated CDKs can phosphorylate the retinoblastoma (RB) protein causing the E2F transcription factor dissociation of from RB.
The activated of E2F can transcribe a number of responder genes (including cyclin E and cyclin A) and promote cell cycle for the
transition from G1 into S. An important response of the normal cell to DNA double-strand blocks (DSBs) is activation of pathways which induce arrest at the G1-S transition. This is so that cells which are in G1 and have suffered DNA damage do not enter S phase, prevents replication of damaged DNA. DNA damage checkpoints operate in the G1, S, and G2 phases of the cell cycle until the damage is repaired.
DNA damage during S phase does not actually stop replication, but instead slows replication if damage has occurred (Rhind & Russell 2000;
Heffernan et al., 2002). The cyclin E/CDK2 complex is required for the transition from late G1 into S. Cyclin A is expressed soon after cyclin E at the G1-S boundary. The binding of cyclin A to CDK2 occurs at the G1-S transition and persists through S phase results in DNA synthesis proceeds. The Cdc2 (also known as CDK1) completed with cyclins A and B is required for progression from G2 into mitosis. The cyclin/CDK1 complexes phosphorylate cytoskeleton proteins including lamins, histone H1, and components of mitotic spindle.
3. Cyclin-dependent kinases inhibitors (CKIs)
Two families of CDK inhibitors are involved in cell cycle regulation.
The first is CIP/KIP (cyclin-dependent kinase-interacting protein/
cyclin-dependent kinase inhibitory protein) family includes the inhibitors p21, p27, and p57. The second family is INK4 (inhibitors of cyclin dependent kinase 4), all contain ankyrin repeats structure, constitutively expressed INK4 genes, includes the inhibitors p16, p15, p18, and p19. The INK4 family of proteins specifically interacts with
CDK4 and CDK6 but not other CDKs. Cells respond to DNA damage by activating cell cycle checkpoints. Several findings have demonstrated that the product of the p53 tumor suppressor gene is responsible for the G1 checkpoint. Recent observations suggest that p53 also plays a role in regulating the G2-M transition. However, it has also been documented that the G2-M transition may be regulated independently from p53, since cells that are p53 nullizygous or with mutated p53 show a DNA damage-induced G2 arrest (Liebermann et al., 1995; Pellegata et al., 1996). DNA damage induced G1, S, or G2 arrest in many cell types by directly and indirectly activating p53 through inhibition of RB phosphorylation. The CIP/KIP family protein (such as p21) at several sites in the cell cycle, targeting CDKs (4, 6, and 2), is response to upregulation by either p53-dependent or -independent mechanisms. As a result of the action of p21, binds to cyclin D/CDK4/6 is inhibited and arrest of cellular proliferation at the checkpoint in G1 or binds to cyclin E/CDK2 causing arrest at the G1-S transition. The increase in p21 followed by inhibition of CDK4 and CDK6 prevents phosphorylation of RB and, as a result, the cell remains in G1 allowing time for DNA repair (Huang et al., 2001; Sheahan et al., 2007). It has also been reported for nontransformed fibroblast cells that p21 transiently colocalizes with cyclin A or cyclin B1 in the nucleus at G2-M (Dash & El-Deiry 2005).
III. Overview of apoptosis