Death receptors are cell surface receptors that transmit apoptotic signals initiated by specific ligands and play a central role in instructive apoptosis. Death receptors belong to the tumor necrosis factor receptor (TNFR) gene superfamily. Eight members of the death receptor family have been characterized so far: TNFR1 (also known as DR1, CD120a, p55 and p60), CD95 (also known as DR2, APO-1 and Fas), DR3 (also known as APO-3, LARD, TRAMP and WSL1), TRAILR1 (also known as DR4 and APO-2), TRAILR2 (also known as DR5, KILLER and TRICK2), DR6, ectodysplasin A receptor (EDAR) and nerve growth factor receptor (NGFR). These death receptors are distinguished by a cytoplasmic region of ~80 residues termed the death domain (DD). When these receptors are triggered by corresponding ligands, a number of molecules are recruited to the death domain and subsequently a signaling cascade is activated. Two types of death receptor signaling complex can be distinguished. The first group comprises the death-inducing signaling complexes (DISCs) that result in the activation of caspase-8, which plays the central role in transduction of the apoptotic signal. DISC is formed at the CD95 receptor, TRAILR1 or TRAILR2. The second group comprises the TNFR1, DR3, DR6 and EDAR. These recruit a different set of molecules, which transduce both apoptotic and survival signals.
The cell cycle is an ordered set of events, culminating in cell growth and division. The cell cycle of eukaryotes can be divided in two brief periods: interphase, during which the cell grows, accumulating nutrients needed for mitosis and duplicating its DNA, and the mitosis (M) phase, during which the cell splits itself into two distinct cells, often called "daughter cells". By studying molecular events in cells, interphase is divided into three stages, G1, S, and G2. Thus the cell cycle consists of four phases: G1, S, G2, M.
G1 phase is from the end of the previous M phase until the beginning of DNA synthesis, and G stands for gap. During this phase the biosynthetic activities of the cell, which had been considerably slowed down during M phase, resume at a high rate. This phase is marked by synthesis of various enzymes that are required in S phase, mainly those needed for DNA replication. An important cell cycle control mechanism activated during this period (G1 Checkpoint) ensures that everything is ready for DNA synthesis.
DNA replication occurs during the ensuing S (synthesis) phase. To produce two similar daughter cells, the complete DNA instructions in the cell must be duplicated. Thus, during this phase, the amount of DNA in the cell has effectively doubled.
The cell then enters the G2 (gap 2) phase, which lasts until the cell enters mitosis. During the G2 phase the cell will continue to grow and produce new proteins. At the end of this gap is another control checkpoint (G2 Checkpoint) to determine if the cell can now proceed to enter M (mitosis) and divide.
After the interphase, during which the cell grows and accumulates nutrients, the cell begins mitosis. Cell growth and protein production stop, all of the cell's energy is focused on the complex and orderly division into two similar daughter cells. As in both G1 and G2, there is a Checkpoint in the middle of mitosis (Metaphase Checkpoint) that ensures the cell is ready to complete cell division.
Nonproliferative cells in multicellular eukaryotes generally enter the quiescent G0 state from G1 and may remain quiescent for long periods of time. The G0 phase is even indefinitely for a cell that has reached an end stage of development and will no longer divide (e.g. neuron).
Early work in frog and invertebrate embryos suggested that cell cycle events are triggered by the activity of a biochemical oscillator centered on cyclin-CDK complexes. The cyclin/CDK complexes induce two processes, duplication of centrosomes and DNA during interphase, and mitosis. The roles of individual cyclins were tested by adding recombinant proteins to cyclin- biologidepleted extracts. Cyclin E supports DNA replication and centrosome duplication, cyclin A supports both of these processes and mitosis, and cyclin B supports mitosis alone. In the cell cycle, Cyclin D/CDK4, Cyclin D/CDK6, and Cyclin E/CDK2 regulate transition from G1 to S phase; Cyclin A/CDK2 is active in S phase; Cyclin B/CDK1 regulates progression from G2 to M phase.
It is widely accepted that the central cell cycle oscillator is based on cyclin/CDK complexes. However, this view of cell cycle regulation was challenged by evidence fora cyclin/CDK-independent oscillator in budding yeast. Haase SB and Reed SI. observed that oscillations of similar periodicity in cells responding to mating pheromone in the absence of G1 cyclin (Cln)- and mitotic cyclin (Clyclin B)-associated kinase activity in the budding yeast Saccharomyces cerevisiae. It is indicated that a previously unrecognized oscillator may play an integral role in regulating early cell cycle events. In addition, Orlando DA and colleagues discovered that a network of sequentially expressed transcription factors could regulate the bulk of the periodic transcription program and function as an oscillator independent of Cyclin B/CDKs.