Download The Cell Cycle

Pathobiology: Introduction and Normal Cell Cycle (Bosch)
BRIEF REVIEW OF INITIATION OF NORMAL CELL REPLICATION:

General:
Normal Cell Replication: occurs in labile and stable cells
Basic Process:
o GF binds to/transiently activates its receptor
o Activation of signal transducing proteins (ie. via phosphorylation) and signal transmission to the
nucleus (directly or indirectly)
o Activation of nuclear transcription regulatory factors  DNA transcription promoting entrance into the
cell cycle (ie. production of cyclin D)

Growth Factors:
Examples:
o Platelet-derived growth factor (PDGF)
o Basic fibroblast growth factor (bFGF)
o Transforming growth factor (TGF)

Growth Factor Receptors:
Examples:
o Epidermal growth factor receptor (EGFR)
o PDGF receptor
o Tyrosine kinase receptor

Signal-Transducing Proteins:
RAS: encodes a family of membrane attached GTP-binding proteins
o Function: transient intracellular signal transduction

GF binds to GFR resulting in activation of RAS proteins (GDP bound  GTP bound)

Stimulation of mitogen-activated protein (MAP) kinase cascade

Nuclear signals for cell proliferation
o Termination of Signal:

GTPase-activating proteins (GAPs) bind to activated RAS proteins (which have intrinsic
GTPase activity), resulting in enhanced GTP hydrolysis

Inactivation of RAS proteins (back to GDP bound) and termination of signal

Note: inactivation of RAS by hydrolysis of GTP can be blocked, resulting in mutant RAS (most
common oncogene)

Nuclear Transcription Regulatory Factors:
MYC: encodes a nuclear protein integral to both cell proliferation and apoptosis
o Function:

GF binds to GFR resulting in mitogenic signal transduction to the nucleus

Rapid induction of MYC and production of the MYC protein

Formation of MYC-MAX protein heterodimers that can bind DNA, leading to the activation of
genes promoting cell division
 Note: cell division is downregulated by MAX homodimers and MAD-MAX
heterodimers

MYC activation WITHOUT GF stimulation (ie. inappropriately activated)  cellular apoptosis

Entrance into the Cell Cycle:
Transcriptional activation of:
o Cyclin D
o CDK4 genes
REVIEW OF NORMAL CELL CYCLE:

Common Theme:
Inactive CDKs bind to cell-cycle specific cyclins resulting in CDK phosphorylation and activation (this process can
be modulated by CDK inhibitors)
Active CDKs phosphorylate key proteins necessary for progression through the cell cycle

Specific Phases of the Cell Cycle:
G0 (resting) and G1 (growth/gap 1) Phases:
o HYPOphosphorylated RB protein bound to E2F TF complex (inhibiting its function)
G1 Phase: organelles double in number
o Synthesis of cyclin D and later cyclin E, resulting in production of D/CDK and E/CDK
o

Phosphorylation of RB protein leading to dissociation from E2F complex and transcriptional activation
of E2F targeted genes (essential for progression through G1/S restriction point)
S (DNA Synthesis) Phase: nuclear DNA is replicated
o Synthesis of cyclin A  formation of phosphorylated A/CDK
G2 (growth/gap 2) Phase: new membranes are made in preparation for cell division
o Synthesis of cyclin B  production of phosphorylated B/CDK  initiation of mitosis
M (mitosis and cytokinesis) Phase:
o Stages: prophase, prometaphase, metaphase, anaphase, telophase
o Completion: characterized by removal of phosphate groups from RB protein (regeneration of
HYPOphsophorylated RB)
Regulation of the Cell Cycle:
CDK Inhibitors: respond to growth suppressing signals
o Block progression of cell cycle
o Inactivate cyclin/CDK complexes OR inhibit their formation (directly or indirectly)
Cell-Cycle Check Points:
o G1/S: checks for DNA defects prior to replication

Detection of DNA damage results in increases levels/activation of p53 protein

Cell cycle arrest via transcriptional upregulation of p21 (which encodes a CDK inhibitor)

Stimulation of DNA repair
 Successful DNA repair: p53-induced transcriptional activation of a protein to
degrade itself and resumed progression through cell cycle
 Unsuccessful DNA repair: p53-induced transcriptional activation of apoptotic genes
(ie. BAX) and repression of pro-proliferative genes/anti-apoptotic genes (ie. cyclins,
BCL2)  apoptosis or senescence
o G2/M: checks for DNA defects after replication and before separation of the chromatids

Detection of DNA damage  cell-cycle arrest via both p53-depedent and independent
processes