2.3 Cell Cycle and Growth Control

The cell cycle is a complex process that governs cell division and growth. It's divided into distinct phases, each with specific events and regulatory mechanisms. Understanding these phases is crucial for grasping how cells replicate and maintain genetic integrity.

Cell cycle control is tightly regulated by various proteins, including cyclins and cyclin-dependent kinases (CDKs). Dysregulation of these control mechanisms can lead to uncontrolled cell growth, a hallmark of cancer. This knowledge is essential for developing targeted cancer therapies and understanding other proliferative disorders.

Cell Cycle Phases and Regulation

Stages of cell cycle

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• Interphase
  • G1 phase (Gap 1) cells grow and prepare for DNA synthesis through protein production and organelle replication (ribosomes)
  • S phase (Synthesis) DNA replicates creating identical sister chromatids while centrosomes duplicate for future mitotic spindle formation
  • G2 phase (Gap 2) cells continue growing and prepare for mitosis by synthesizing proteins needed for chromosome segregation (tubulin)
• Mitosis (M phase)
  • Prophase chromosomes condense and become visible while nuclear envelope breaks down exposing genetic material
  • Metaphase chromosomes align at cell's equator attached to spindle fibers from opposite poles
  • Anaphase sister chromatids separate and move to opposite poles of the cell pulled by shortening spindle fibers
  • Telophase nuclear envelope reforms around separated chromosomes which begin to decondense
• Cytokinesis cytoplasm divides through contractile ring formation (animal cells) or cell plate formation (plant cells) creating two daughter cells

Regulation by cyclins and CDKs

• Cyclin-CDK complexes drive cell cycle progression through phosphorylation of target proteins
• Cyclins regulatory subunits with fluctuating levels throughout cell cycle (Cyclin D, E, A, B)
• CDKs catalytic subunits activated by cyclin binding remain at constant levels (CDK1, 2, 4, 6)
• Key cyclin-CDK complexes
  • Cyclin D-CDK4/6 promotes G1 progression by phosphorylating Rb protein
  • Cyclin E-CDK2 triggers G1/S transition by activating DNA replication machinery
  • Cyclin A-CDK2 ensures S phase progression and prevents re-replication of DNA
  • Cyclin B-CDK1 initiates G2/M transition by phosphorylating nuclear lamins
• Cell cycle checkpoints
  • G1/S checkpoint ensures DNA integrity before replication through p53 activation
  • G2/M checkpoint verifies DNA replication completion and cell size adequacy
  • Spindle assembly checkpoint ensures proper chromosome attachment to spindle before anaphase onset

Cell Cycle Control and Cancer

Cell cycle arrest mechanisms

• DNA damage response
  • ATM and ATR kinases sense DNA breaks and activate downstream effectors
  • p53 activation leads to transcriptional upregulation of p21 causing G1/S arrest
• Cellular stress response triggers cell cycle arrest under unfavorable conditions
  • Oxidative stress activates p38 MAPK pathway leading to p53-independent G2/M arrest
  • Nutrient deprivation activates AMPK pathway inhibiting mTOR and cell cycle progression
  • Hypoxia stabilizes HIF-1α inducing p21 expression and G1 arrest
• p53-mediated apoptosis when damage is irreparable
  • Transcriptional activation of pro-apoptotic genes (BAX, PUMA, NOXA)
  • Mitochondrial outer membrane permeabilization releases cytochrome c
• Caspase activation cascade leads to controlled cell dismantling
  • Initiator caspases (caspase-9) activated by cytochrome c release
  • Effector caspases (caspase-3, -7) cleave cellular proteins leading to apoptotic cell death

Dysregulation in cancer

• Hallmarks of cancer related to cell cycle
  • Sustained proliferative signaling through constitutive activation of growth factor pathways (EGFR mutations)
  • Evasion of growth suppressors by inactivation of tumor suppressors (p53, Rb)
  • Resistance to cell death through upregulation of anti-apoptotic proteins (Bcl-2)
• Common cell cycle alterations in cancer
  • Cyclin D1 overexpression promotes G1/S transition in breast and esophageal cancers
  • CDK4 amplification leads to uncontrolled proliferation in melanoma
  • p16 inactivation removes inhibition on CDK4/6 in various cancers
  • Rb protein dysfunction allows unrestricted E2F-mediated transcription
• Consequences of cell cycle dysregulation
  • Uncontrolled cell division leads to tumor formation and metastasis
  • Genomic instability results from compromised DNA repair and checkpoint functions
  • Aneuploidy arises from chromosome missegregation during aberrant mitosis
• Cell cycle targets in cancer therapy
  • CDK inhibitors (palbociclib) block G1/S transition in hormone receptor-positive breast cancer
  • Mitotic spindle poisons (paclitaxel) disrupt microtubule dynamics in various solid tumors
• Other proliferative disorders
  • Benign tumors exhibit controlled growth without invasion (uterine fibroids)
  • Hyperplasia involves increased cell number in tissue (benign prostatic hyperplasia)
  • Psoriasis characterized by rapid keratinocyte turnover due to inflammatory signals