july_19_2010_Cancer_Cell_Biology_1

Cell cycle and cancer

Summary

?Phases of the Cell Cycle

?Interphase

?Mitosis

?Cytokinesis

?Cell Cycle Control

?Cancer

Cell Division in Prokaryotes

?Prokaryotic cell division occurs as binary fission in which cell divides into two halves. –Genetic information exists as a single,

circular double-stranded DNA molecule.

?Copying begins at replication origin, and proceeds bi-directionally.

One genome ends up in each

daughter cell. 4

Phases of the Cell Cycle

?Five phases of cell division:

–G 1 - primary growth phase

–S - genome replicated

–G 2 - secondary growth phase

?collectively called interphase

–M - mitosis

–C - cytokinesis

Cell Cycle

Restriction point 6

Interphase

?G 1 - cells undergo majority of growth

?S - each chromosome replicates to produce sister chromatids

–attached at centromere

contains attachment site (kinetochore )

?G 2 - chromosomes condense

–assemble machinery such as centrioles

7 8

Mitosis

?Prophase

–spindle apparatus assembled

Microtubules connect kinetochores on

each pair of sister chromatids to the

spindle poles.

–nuclear envelope breaks

Mitosis

?Metaphase

–chromosomes align in cell’s center

?metaphase plate

spindle

11 12

Mitosis

?Anaphase

–sister chromatids pulled toward poles

?poles move apart

?centromeres move toward poles

microtubules shorten

?Telophase

–spindle disassembles

–nuclear envelope forms around each set of sister chromatids

Prophase Metaphase Anaphase

Telophase

Figure 8.3a The Biology of

Cancer (? Garland Science

2007)

Figure 8.3b The Biology of

Cancer (? Garland Science

2007)

CH4細胞週期(The Cell Cycle) CH4細胞週期(The Cell Cycle)

Cytokinesis

?Cleavage of cell into two halves

–animal cells

?constriction belt of actin filaments –plant cells

?cell plate

–fungi and protists

?mitosis occurs within the nucleus

Cytokinesis

Cell Cycle Control

?Two irreversible points in cell cycle:

–replication of genetic material

–separation of sister chromatids

?Cell can be put on hold at specific checkpoints. 20

Cell Control Cycle

?G 1 / S - primary division decision point ?G 2 / M - commitment to mitosis

?Spindle checkpoint - all chromosomes are attached to spindle

Growth Factors and the Cell Cycle

?Each growing cell binds minute amounts of positive regulatory signals (growth factors ) that stimulate cell division.

–If neighboring cells use up too much

growth factor, there is not enough left to

trigger cell division.

?Growth factors trigger intercellular

signaling systems. 22

Cancer and Cell Proliferation

?Cancer is essentially a failure of cell division control (unrestrained, uncontrolled cellular growth).

–gene p53 plays a role in G 1 checkpoint

?halts cell division if detects damaged

DNA and stimulates activity of repair

enzymes

?appears to be absent in many

cancerous cells

External Signals Influence a Cell’s Decision to Enter into the Active Cell Cycle

?Cell division-mitosis and cytokinesis ?Mitogen and growth-inhibitory factors ?Mitogen drives cells from G 0 into G 1 ?Cell in G 1 make critical decisions about growth versus quiescence

Cell Cycle Checkpoints

?G1/S

–Monitors cell size and for DNA damage

?G2/M

–Replication complete, DNA damage?

–Spindle fibers connected, etc.?

?G0

–Does body require more of my type of cell?

Figure 8.6 The Biology of Cancer (? Garland Science 2007)

三、细胞周期的调控(regulation

of cell cycle)

2.Cell cycle checkpoint

cyclin(周期素)：是一种调节性蛋白质。

Cdks (cyclin-dependent kinase)

MPF: Maturation Promoting Factor,其活性受cyclin 调控。

Cell-cycle 控制系统：在细胞周期中可接受〝stop〞或〝go-ahead〞信息而调控的点。

CYCLINS

- no intrinsic enzymatic activity

- binds cdk

- synthesized and degraded each cycle

- essential component for cdk activity

e.g. Cyclin B

Cyclins and Cyclin-dependent Kinases Constitute the Core Components of the Cell Cycle

Clock

?Cyclins control cyclin-dependent kinase (CDK) in the progress of cell cycle transition ?Usually stability of cyclins is responsible for

CDK activity to regulate transition of cell cycle ?The various combination of cyclins and CDKs

appear in the different phase of cell cycle

Regulators of Cell Cycle

?Cyclins and cyclin-dependent kinases (CDKs) ?Cyclins synthesized and destroyed in a precise pattern

–A cyclin bind to a specific CDKs, activating it

?Other proteins phosphorylated/activated

?CDK4/cyclinD activate transcription factors for genes

such as DNA polymerase delta and DNA ligase

?CDK1/cyclinB trigger events of early mitosis

(chromosome condensation, nuclear membrane

breakdown, etc.) CYCLIN/CDK

tyr15-P P-thr161 thr14-P

cdk1

(cdc2)

cyclin B

Regulated by:

-tyr15 phosphorylation ? inhibitory kinases

? activating phosphatases

-direct interaction

? inhibitory proteins

?e.g. p21, p27, p57 ?p16, p15, p18,p19

Cyclin Levels Activation

of CDKs

Figure 8.8 The Biology of Cancer (? Garland Science 2007)

Regulation of activity of CDKs

?The most important way of achieving regulation of activity of CDKs depends upon changing the levels and stability of cyclins during various phase of cell cycle

Figure 8.12 The Biology of Cancer (? Garland Science 2007)

After R point, cell cycle machinery takes on a life of its own that is quite autonomous and no longer responsive to extracellular signals

Cyclin-CDK Complexes are also Regulated by CDK Inhibitors ?Four proteins, p16INK4A

, p15INK4B ,

p18INK4C , and p19INK4D

named as the INK4 proteins (in hibitors of CD K4), are targeted specifically to the CDK4 and CDK6 complexes. ?Three other CDK inhibitors, p21Cip1,

p27Kip1, and p57Kip2, are more widely acting, being able to inhibit all other cyclin-CDK complexes that form at later stages of the cell cycle

Figure 8.13a The Biology of Cancer (? Garland Science 2007)

TGF-b

= Tumor suppressor

CELL CYCLE CHECKPOINTS ◆MITOSIS ENTRY (G2/M) ◆Replication Complete

◆Growth/ Protein Synthesis adequate

◆No DNA Damage

◆S-PHASE ENTRY (G1/S)

◆Mitosis Complete ?signal - cyclin degradation

◆Growth/ Protein Synthesis (G1 CYCLINS)

◆No DNA Damage

◆OTHERS

◆MITOSIS EXIT: ?coupling to S-phase

◆S PHASE : coupling to mitosis

◆also in response to DNA damage

◆G1 sequence of events

◆signaling from cell surface

Figure 8.4 The

Biology of Cancer (?

Garland Science

2007)

The Cells deploys a series of surveillance mechanisms, checkpoints, to prevent genome from damage

Cells Make Decisions about Growth and Quiescence During a Specific Period in the G1 Phase

?G 1 represents the status for responding to

mitogens and TGF-b signaling to make decision whether or not cell cycle to proceed

?The critical decision is made at a transition, named as restriction point (R point)

?The commitment through R point entering S will, unless a major disaster, invariably complete S, G 2 and toward M phase

?Deregulation of the R point decision-making accompanies the formation of most if not all types of cancer cells

Figure 8.9 The Biology of Cancer (? Garland Science 2007)

? Cell cycle-dependent fluctuations

in cyclin B levels