Fundamentals of Cell Biology

Chapter 13: The Birth and Death of Cells

• Chapter foci: – How cells make the decision to begin moving

through the stages of replication, and why some cells never make this journey

– How cells decide to die

Chapter Summary: The Big Picture (1)

Chapter Summary: The Big Picture (2)

• Section topics:– New cells arise from parental cells that

complete the cell cycle– Multicellular organisms contain a cell self-

destruct program that keeps them healthy

New cells arise from parental cells that complete the cell cycle

• Key Concepts (1):– Cells divide by following carefully scripted program of molecular

events collectively called the cell cycle.

– The cell cycle is subdivided into five phases named G1, S, G2, M, and G0. Cells not actively dividing reside in G1 or G0 phase.

– Progression through the cell cycle is under the control of proteins that form checkpoints to monitor whether the proper sequence of events is taking place. Cells halt at these checkpoints until they complete the necessary steps to continue.

New cells arise from parental cells that complete the cell cycle

• Key Concepts (2):

– The G1/S checkpoint, called the restriction point or start point, is where cells commit to completing cell division. Proteins called cyclins play an important role in advancing cells through checkpoints.

– Cell division takes place in ten steps.

The cell cycle is divided into five phases

• “Resting” cells reside in G0 or G1 phase

• Several checkpoints define critical decision-making events in the cell cycle

Figure 13.01: The cell cycle.

Figure 13.02: Checkpoints

control progression through the

cell cycle. Some of the

major checkpoints are shown.

“Point of no return”

The G2/M checkpoint is the trigger for large-scale rearrangement of cellular architecture

• MPF

Figure 13.03: Early experiments characterizing the activity of Mitosis Promoting Factor.

Activation of cyclin-CDK complexes begins in G1 phase

Figure 13.04: Scientists discovered the first cyclins when they noted that high cyclin levels with the onset of mitosis in embryos. Cyclin levels drop sharply after this.

Control by cyclin/CDK complexes

Figure 13.05: Distinct cyclin-cdk complexes control progression through cell cycle checkpoints.

Cell cycle step 1: Signal transduction initiates cell cycle progression.

Figure 13.06: The family of mitogen activated protein kinases (MAPKs) and their upstream regulatory proteins.

Figure 13.07: A simplified MAP kinase signaling pathway.

Cell cycle step 2: Changes in gene expression are required for progression

through the restriction point

• progression through the restriction point in mammalian cells requires activation of at least two cyclin/CDK complexes: cyclin D1/CDK4 (or CDK6) and cyclin E/CDK2

• expression of most CDKs does not vary much throughout the cycle, but without their corresponding cyclins, they are not functional

Cell cycle step 3: Pro- and anti-growth signaling networks converge at the G1/S

cyclin-CDK complexes

• Phosphorylation• Binding by inhibitory

kinases• Subcellular location• Protein degradation

Figure 13.08: Summary of the cyclin/cdk activation-inactivation cycle.

Cell cycle step 4: Active cyclin/CDKs phosphorylate pocket proteins, which

activate E2Fs

Figure 13.09: The transcription factor E2F is inactivated by Rb

binding.

Figure 13.10: Examples of positive (green) and negative (red) feedback loops controlling E2F

function.

How E2Fs enhance expression of some genes while suppressing

expression of others remains unclear

Figure 13.11: A model of how E2F transcription factors can suppress or activate gene transcription.

Cell cycle step 5: The DNA replication machinery is activated by protein kinases

Figure 13.12: Assembly of the prereplication complex.

DNA replication occurs in S phase

• 3 key steps

Figure 13.13: Activation of the replication complex.

Cell cycle step 6: DNA integrity is ensured by the G1/S, S/G2, and G2/M checkpoints

Figure 13.14: A current model for DNA repair.

Figure 13.15: Growth arrest induced by Chk1 and Chk2.

Cell cycle step 7: Cells increase in size during G2 phase

Figure 13.17: Wee1 mutation affects cell size. Compared to normal ("wild-type," WT) yeast, Wee1 mutants grow to half normal size before dividing.

Cell cycle step 8: Cyclin B/CDK1 activation drives cells through the G2/M checkpoint

Figure 13.18: A model for cell size control of cell growth in yeast in G2.

Figure 13.19: A model for how adhesion to ECM promotes cell growth

in mammalian cells.

Figure 13.20: Phosphorylation of Cdk1 primes it for activation but also keeps it in an inactive state.

Cell cycle step 9: Chromosome alignment is ensured by the mitotic spindle assembly

checkpoint

Figure 13.21: A model for anaphase promotion by APC/C.

Cell cycle step 10: Onset of cytokinesis is timed to begin only after mitosis is complete

• Cytokinesis requires the contraction of the contractile ring that lies just beneath the plasma membrane, perpendicular to the long axis of the mitotic spindle.

• It is important that the myosin motors in the ring not activate until mitosis, including reconstitution of the nuclear membrane, is complete.

Multicellular organisms contain a cell self-destruct program that keeps them healthy

• Key Concepts:– Cells die either by traumatic injury (necrosis) or by a

self-destruct program called apoptosis. – Apoptosis begins through at least two molecular

mechanisms, called intrinsic and extrinsic pathways.– The family of proteins called caspases includes

proteases that promote the degradation of organelles and cytosolic proteins during apoptosis.

Cells die in 2 different ways: necrosis and apoptosis

Figure 13.22: Cellular damage can result in necrosis, as organelles swell and the plasma membrane ruptures.

Apoptosis is a property of all animal cells and some plant cells

Apotosis is voluntary

Figure 13.23: Sections of the interdigital web show cell death (dark-staining nuclei). This cell death has the characteristics of apoptosis.

Apoptosis is induced via at least 2 different pathways

Figure 13.24: Ligation of death receptors causes the recruitment of the adaptor

protein FADD to the intracellular region of the death receptor.

Figure 13.25: E2F1 lies at the heart of the growth-versus-death decision making

system.

Targets of pro- and anti-apoptotic transcription factors are members

of bcl-2 family

Figure 13.26: The Bcl-2 family proteins share up to four Bcl-2 homology domains

(BH) and can be antiapoptotic or proapoptotic.

Figure 13.27: The Bcl-2 family of proteins compete with members of the

antiapoptotoic group to access the apoptotic group in an elaborate hierarchy.

Mitochondrial Outer Membrane Permeabilization (MOMP)

Figure 13.28: Signals for the induction of apoptosis trigger changes in the Bcl-2 family proteins, which function to inhibit or promote apoptosis. Activation of caspase 9 by the apoptososme. Insert, three views of apoptosome

structure as determined by electron microscopy.

Apoptosis triggers the activation of special proteases: the caspases

Figure 13.29: Different types of vertebrate caspases are shown schematically.

The final changes

• Stereotypical morphological changes take place during apoptosis– karyorrhexis

• Apoptotic cells are cleared by phagocytosis