Cell Cycle Regulation, Mitosis, and Apoptosis

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Cell Cycle and Mitosis

Overview of the Cell Cycle

The cell cycle is a series of events that cells go through as they grow and divide. It consists of interphase (G1, S, G2) and the mitotic (M) phase, which includes mitosis and cytokinesis.

Interphase: The cell grows (G1), replicates its DNA (S), and prepares for division (G2).
Mitosis (M phase): The shortest phase, where the cell divides its chromosomes and cytoplasm to produce two daughter cells.
Checkpoints: Critical control points where the cell verifies whether key processes have been completed before progressing.

Phases of the Cell Cycle

G1 phase: Cell growth and production of cellular components.
S phase: DNA synthesis and replication.
G2 phase: Final preparations for mitosis; checks for DNA damage and completeness.
M phase: Includes prophase, prometaphase, metaphase, anaphase, telophase, and cytokinesis.

Mitosis: Stages and Key Events

Mitosis ensures equal distribution of chromosomes to daughter cells. The stages are:

Prophase: Chromosomes condense, spindle forms.
Prometaphase: Nuclear envelope breaks down, spindle fibers attach to chromosomes.
Metaphase: Chromosomes align at the cell equator.
Anaphase: Sister chromatids separate and move to opposite poles.
Telophase: Nuclear envelopes reform, chromosomes decondense.
Cytokinesis: Division of the cytoplasm, forming two daughter cells.

Cell Cycle Checkpoints and Regulation

Major Checkpoints

Checkpoints ensure the fidelity of cell division and prevent damaged cells from proliferating.

G1/S checkpoint: Checks for cell size, nutrients, growth factors, and DNA damage before DNA replication.
G2/M checkpoint: Ensures DNA replication is complete and checks for DNA damage before mitosis.
Metaphase/Anaphase checkpoint: Verifies that all chromosomes are properly attached to the spindle before separation.

Experimental Evidence for Cell Cycle Control

Heterokaryon experiments: Fusion of cells at different cycle stages showed that S or M phase cells contain factors that can induce progression in G1 cells.
Frog egg experiments: Cytoplasmic factors from meiotic cells (MPF) can induce meiosis in immature eggs.

Maturation Promoting Factor (MPF)

MPF is a protein complex that triggers entry into M-phase. Its activity peaks as the cell enters mitosis.

Composed of a cyclin and a cyclin-dependent kinase (cdk).
MPF activity is regulated by cyclin levels and phosphorylation events.

Molecular Control of the Cell Cycle

Cyclins and Cyclin-Dependent Kinases (CDKs)

Cyclins are regulatory proteins whose levels fluctuate during the cell cycle. CDKs are kinases that, when bound to cyclins, phosphorylate target proteins to drive cell cycle progression.

CDK activity depends on cyclin binding and specific phosphorylation events.
Example: cdc2 (CDK1) identified in yeast as essential for M-phase entry.

Activation and Regulation of Cyclin-CDK Complexes

Formation of cyclin/CDK complex is necessary but not sufficient for activation.
Regulation involves addition and removal of inhibitory and activating phosphate groups:

Kinases add inhibitory phosphates.
Activating kinase adds an activating phosphate.
Phosphatase removes inhibitory phosphates, fully activating the complex.

Equation:

Role of Cyclin Degradation

At anaphase, cyclin is degraded by the anaphase-promoting complex (APC), triggering chromatid separation.
Cyclin levels rebuild in subsequent cycles.

Checkpoint Control by Tumor Suppressor Genes

Retinoblastoma protein (Rb): Inhibits transcription factor E2F, preventing S-phase gene expression.
p53: Activated by DNA damage, induces cell cycle arrest or apoptosis by expressing inhibitors of cyclin/CDK complexes.
Both Rb and p53 are tumor suppressor genes.

Growth Factors and Cell Cycle Progression

Growth Factor Signaling Pathways

Growth factors (GFs) are external signals required for cell cycle progression, especially at the G1/S transition.

GFs bind to cell surface receptors, activating the Ras-MAPK pathway.
MAPK (mitogen-activated protein kinases) activate transcription of early genes (e.g., Myc), which in turn activate late genes (e.g., E2F, G1 cyclin, CDK).
Ras and Myc are oncogenes; their dysregulation can lead to cancer.

Growth Factor Pathway Table

Component	Function
Growth Factor	External signal for cell cycle entry
Receptor	Binds GF, activates intracellular signaling
Ras	GTPase, initiates MAPK cascade
MAPK	Activates transcription factors (e.g., Myc)
Myc	Early transcription factor
E2F	Drives S-phase gene expression

Apoptosis and Cell Cycle Control

Apoptosis: Programmed Cell Death

Apoptosis is a genetically regulated process that eliminates damaged or unnecessary cells.

Triggered by checkpoint activation (e.g., p53) or inhibitory receptor signaling.
Involves nuclear fragmentation, cytoplasmic condensation, and formation of apoptotic bodies.
Phagocytic cells remove apoptotic bodies.

Genetic Regulation of Apoptosis

Key discoveries made in C. elegans (nematode).
2002 Nobel Prize awarded for work on genetic regulation of organ development and programmed cell death.

Cell Cycle Dysregulation and Cancer

Consequences of Checkpoint Failure

Dysregulation of cyclins, CDKs, or tumor suppressors (Rb, p53) can lead to uncontrolled cell division and cancer.
Oncogenes (e.g., Ras, Myc) promote cell cycle progression; mutations can result in malignancy.

Summary Table: Key Regulators of the Cell Cycle

Regulator	Role	Associated Phase/Checkpoint
Cyclin/CDK	Drives cell cycle progression	G1/S, G2/M, Metaphase/Anaphase
Rb	Inhibits E2F, blocks S-phase entry	G1/S
p53	Induces cell cycle arrest/apoptosis	G1/S, G2/M
APC	Degrades cyclin, triggers anaphase	Metaphase/Anaphase
Growth Factors	Stimulate cell cycle entry	G1/S