Cell Cycle And Cancer

Front 1

Phases of cell cycle

Back 1

G1: variable amount of time, can decide if it wants to apoptosis (die), proliferation (rest of cell cycle), senescence (not moving through cycle, Go) differentiation (Go)

S: synthesis of chromatin (histone proteins made, 2NDNA becomes 4NDNA)

G2: preparation for M phase, centrosome duplicates

M: mitosis

Front 2

Tg

Back 2

Total generation time, one cycle through cell cycle

Variable because G1 length varies, whereas S, G2 and M are 12-24 hrs

Front 3

Proteins regulating cell cycle

Back 3

Externally: how it begins initially; ytokines, growth factors

Internally: early response factors like myc, fos, jun; delated response factors like cyclin dependent proteins (cyclin + cdk)

Front 4

Cyclin dependent proteins

Back 4

Made of:

cyclin--regulatory subunit, different kinds of it peak during cell cycle

CDK--catalytic subunit that phosphorylates proteins; content won't change during cell cycle; attaches PO4 to serine, threonine and tyrosine

Front 5

Types of cyclin and times when highest

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Cyclin D: highest in G1 and stays high

Cyclin E: breaches restriction check point to be highest during S

Cyclin A: highest in S phase and sustains it

Cyclin B: highest in G2, makes transition to M

Front 6

Three types of CDK and when used

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CDK-4: in G1

CDK-2: in S

CDK-1: in G2 to M

Front 7

Initial Induction of Cell Cycle

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In G1 or G0, p27 decreases because it normally inhibits CDK

Cyclin D increases and turns on CDKs

Front 8

Cell Checkpoints

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Areas of regulations in cell cycle

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Cell Checkpoint 1: early G1, cyclin D/CDK4

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1. Growth factor to myc to cyclin D

2. cyclin D binds to CDK-4

3. cyclin D/CDK-4 complex phosphorylates RB, a tumor suppressor protein that inhibits cycle by holding onto E2F

4. Phosphorylated Rb drops transcription factor E2F

5. E2F activates genes that encode for cyclin E and cyclin A

Front 10

Cell Checkpoint 2: before S, restriction site! Cyclin E/CDK 2

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Cell becomes committed to dividing after this, no other extracellular regulators are needed

1. Cyclin E binds to CDK2

2. Cyclin E/CDK 2 complex phosphorylates target proteins

If need to stop: p53 can induce p21, which binds to CDK2 so cyclin E can't

Front 11

Cell Checkpoint 3: Cyclin A/CDK 2

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Helps through S phase

1. Cyclin A binds to CDK2

2. Cyclin A/CDK2 phosphorylate proteins in DNA replication

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Cell Checkpoint 4: Cyclin B/CDK 1

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In G2/M phase

1. Phosphatase cdc 25 dephosphorylates CDK1 heterodimer unit

2. cyclinB/CDK1 goes into nucleus, where it causes multiple phosphorlations that:

a. break nuclear envelope

b. assemble mitoic spindle

c. cause metaphase arrest

Front 13

Characteristics of cancer

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- Genetic disease caused by point mutations or chromosome rearrangements that deactivate/activate proteins

- Proteins mutated often aid in cell cycle, mutations accumulate overtime and cause maligancy

- cell differentiation decreases, proliferation increases (usually the opposite)

- metastatic spread occurs

Front 14

Name the 5 Gene Grps Mutated in Cancer

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1. Proto-oncogenes

2. Tumor suppressor genes

3. Genes that regulate apoptosis

4. Genes that regulate cell senescence

5. DNA Repair Genes

Front 15

Mutations in Proto-oncogenes

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Proto-oncogenes are normal genes that encode receptors for growth factors, cyclins and CDKs; become oncogenes when mutated; cause overactivation and abnormal cell stimulation

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Types of Proto-oncogenes (examples)

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Cell membrane growth factor receptors

EGFR (causes lung carcinoma)

Src tyrosine kinase receptor (causes sarcoma/colon cancer)

Cytoplasmic transcription factors

Ras (GTPase in 25% of cancers)

Myc (Burkitt's lymphoma)

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Mutations in tumor suppressor genes (we have 20)

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Mutation causes loss of suppressor function of cell by inactivation

-p21

-p53 (cigarette smoke mutates, Advexin tries encoding normal copy)

-Rb

-BRCA-1 and BRCA-2 (repair bad DNA, huge cause of breast cancer)

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Mutations in genes that replicate apoptosis

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Mutation of genes that cause cell death so it can't occur (B cell lymphoma w/bcl-2 gene)

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Steps of apotosis:

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1. macrophages secrete TNF

2. TNF binds to TNF receptor

3. TNF receptor balances pro and anti apoptotic factors

4. pro apototic factors cause the cytochrome C to leak to cytoplasm, which activates captase that eats up chromatin and explodes cell

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Mutations in Genes that Regulate Senescence

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Example: telomerase

Telomerase keeps telomere length same in sex cells, not somatic cells

When mutated in somatic cells, cell is immortal

Front 21

Mutations in DNA Repair Genes

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Without repair mechanisms, the mutations pile up and the bad cells replicate

Example: BRCAs, colo-rectal cancer

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Prevention of Cancer

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Test for BRCA mutations, or bladder/prostate cancer antigens

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Current treatment of Cancer

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non specific

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Ideas for specific treatments of cancer:

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1. target metastasis (inhibit metallo proteases, which eat tissues so tumors can move)

2. target angiogenesis (prevent blood vessel growth of tumor)

3. target specific molecules

-tumor cell inhibitors (CD20 in B cell lymphoma, herceptin in breast cancer)

-activate, replace p53 (with Advexin)

-destroy pathogenic RNAs via siRNA therapy