EFB325 Cell Physiology

Regulation of the cell cycle

Cells arise by division of an existing, living cell

• This may seem like a simple concept, but this was discovered only in the mid-1800's.
• Cells today have arisen from a continuous series of cell divisions since the first living cells divided
• Cell division (mitosis) gives rise to two genetically identical daughter cells

Cell division occurs as a cycle of different phases and regulatory points=cell cycle

In general terms, we can describe cell status as being in the process of division or in interphase.

• during interphase, the cell grows, performs its metabolic function, and replicates its chromosomes in preparation for another division

These can be further subdivided and named:

-the division phase is named M (mitotic) phase and includes: mitosis (nuclear division) and cytokinesis (cell division)

-interphase is divided into G1 (gap 1), S (synthesis), and G2 (gap 2) phases

G1 (gap 1)

• phase in which daughter cells are growing and functioning; the cells are 2n and 2c (they are diploid and have 2 copies of each of the chromosomes)

S (synthesis)

• DNA replication occurs, making duplicate copies of each of the chromosomes in preparation for cell division (each chromosome consists of 2 sister chromatids which are tightly bound to each other)
• the cells are 2n and 4c (they are diploid, but have 4 copies of each chromosome)

G2 (gap 2)

• the cells may grow more at this point
• at the end of G2, chromosomes begin to condense in preparation for cell division

There are points in these phases when a cell will stop and "decide" whether to continue on through the cell cycle=cell cycle checkpoints

There are two checkpoints: at the end of G1 (controls the start of chromosome replication) and at the end of G2 (controls the start of mitosis)

• the cell cycle can come to a halt at these points (and not finish cell division)
• the "decision" to proceed can be determined by cell growth (linked to nutrition), environmental factors, and proper replication of DNA

"Molecular triggers" measure the passage through the cell cycle and control progress through the checkpoints, these triggers are kinases that require an additional protein subunit (cyclin):

• cyclin proteins accumulate through interphase and are degraded during mitosis (M phase)
• cyclin-dependent kinase (Cdk) associates with cyclin to form a complex
• the cyclin-Cdk complex becomes activated by phosphorylation and dephosphorylation of the Cdk at the end of G2. The active cyclin-Cdk complex is called M-phase-promoting factor (MPF) and triggers the cell to proceed into M phase
• cytoplasm from a dividing cell (like a frog oocyte) can be injected into a cell in G1 and MPF will stimulate mitosis

There are actually different Cdks and cyclins active at different points in the cell cycle

• there is a G1 cyclin-Cdk complex that act early in G1 phase and help to activate the S phase cyclin-Cdk complex, especially in response to growth factors
• there is a S phase cyclin-Cdk complex that triggers the cells to enter S phase
• there is a mitotic cyclin-Cdk complex that triggers the cells to enter M phase

Regulation of growth, the cell cycle, and programmed cell death

Most cells in the human body are not in the process of dividing. Cell division generally only occurs at the rate necessary to replace cells that are lost, which varies from tissue to tissue. We use the cell cycle to describe the phases of cell division, but what controls the cell cycle? How is a cell triggered to proceed (or not) through the steps of cell division.

Different cell types have variations in the timing, control, and progression through the cell cycle

• most cells in the human body are not actively dividing and some never divide again after they have differentiated (they are in G₀ phase, a type of resting phase)
• stem cells are constantly dividing [bone marrow cells, epithelial cells (like lining of intestine), skin cells]
• nerve cells and muscle cells do not divide after they are differentiated; liver cells divide approx. once per year
• other cells are triggered (by growth factors) to divide to replace adjacent cells that have died

Cells require signals to proceed through the cell cycle

• mitogens - stimulate progress past checkpoints and promote mitosis
• growth factors - stimulate cellular growth in size by promoting synthesis and inhibiting degradation
• survival factors - repress programmed cell death (see below)

What do the cyclin-dependent kinases actually do to promote the cell cycle? (What are their substrates?)

• S-Cdk can phosphorylate and inactivate a repressor of DNA replication
• M-Cdk can phosphorylate the nuclear lamins, which leads to the disassembly of the nuclear lamina
• M-Cdk can phosphorylate microtubule-associated proteins, leading to mitotic spindle formation
• M-Cdk can trigger chromosomes to condense and triggers separation of sister chromatids during anaphase
• G1-S-Cdk can also phosphorylate and thus inactivate a master gene inhibitor protein=Rb protein

Cell proliferation is inhibited by the Rb protein (Rb=retinoblastoma)

• Rb normally represses the transcription factors needed for expression of genes used in cell proliferation
• when the cell perceives a growth factor hormone, the G1 cyclin-Cdk complexes become active and these phosphorylate and thus inactivate Rb
• with Rb inactive, the genes for cell proliferation are expressed

The "health" of the cell is monitored by the p53 protein

• p53 checks for DNA damage and other cellular damage (like oxygen deprivation)-when there is DNA damage, p53 becomes active
• active p53 acts as a transcription factor to stimulate expression of p21 protein
• p21 protein is a Cdk inhibitor protein, it binds and inhibits cyclin-Cdk complexes, thus bringing the cell cycle to a halt
• p53 can also trigger the cell to commit suicide if the damage is severe (for example if the telomeres have become too short); this suicide process is a controlled disassembly of the cell=programmed cell death
• if chromosomes are not properly attached to mitotic spindles, programmed cell death is triggered

Programmed cell death (also called apoptosis) is the definate end of cell proliferation and allows a controlled disassembly of cellular materials

• cellular DNA is degraded in a controlled manner and proteins are cleaved by proteases to release amino acids
• apoptotic cells are engulfed by phagocytes to further digest and recover cellular materials
• apoptosis occurs as a normal component of development - for example in the death of cells between digits during mouse paw development; in the hormonally triggered death of the tadpole tail; in the death of xylem cells in plants during their maturation
• survival factors act to repress apoptosis

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