Growth Control

Question 1

growth control

Answer 1

• cells within different tissues of multicellular organisms divide at different times and rates
• rapid in small intestine, epidermis
• slow/never in neurons and cardiac muscle
• intermittent in vascular cells during wound repair
• controlled by:
  1. cell lineage
  2. external diffusible factors
  3. cell cell/cell-ECM interactions

Question 2

cell lineage

Answer 2

• internal control of G1/S transition
• apoptosis- occurs during natural development
• checkpoint error

Question 3

apoptosis during normal development

Answer 3

1. formation of digits- defect is syndactyly
2. epithelial cells during palate fusion
3. neurons in developing brain
   also occurs in normal adult cells
4. lining of gut
5. mammary tissue post lactation

Question 4

control of neuron number during development

Answer 4

• start with more nerve cells than targets
• most cells require signals to stay alive
• others die off via apoptosis

Question 5

morphology

Answer 5

• apoptotic cells shrink, form membrane blebs, and fragment
• release small membrane bound apoptotic bodies that are phagocytosed by macrophages
• intracellular contents aren’t released-prevents IF
• necrotic cells swell and burst and release inside contents

Question 6

signaling and apoptosis-intrinsic pathway

Answer 6

1. in absence of trophic factors, pro-apoptotic factor Bad can interact with anti-apoptotic proteins BCL2 and Bclcl in outer mito membrane
2. this blocks their inhibitory interaction with Bax and permits formation of Bax containing channels and the release of cytochrome c from mito
3. results in activation of caspases (from cleavage of procaspases), which generates proteolytic amplification cascade
4. caspases digest important intracellular structural proteins such as lamins and cytoskeleltal proteins, leading to demise and fragmentation

Question 7

terminal differentiation

Answer 7

• cells stop dividing
• neurons, cardiac cells
• significant barrier to recovery from spinal cord injury or heart disease
• mature cells of skin/ gut

Question 8

senescence

Answer 8

• cells in culture stop dividing after 50-100 divisions
• due to absence of telomerase-ribozyme that adds 6 base repeating seq of non-coding DNA to ends of chromosomes (telomeres)
• allow for complete replication of lagging strand
• most somatic cells in adult tissues lack telomerase
• when they get too short, stop replicating
• limits unwanted proliferation and protects cells from replicating incomplete chromosomes

Question 9

growth factors

Answer 9

• concentration and cell type specific
• some act locally-PDGF- released from activated platelets and stimulates wound repair
• epidermal. endothelial cell migration/proliferation
• some act systemically- EPO stimulates RBC differentiation in bone marrow

Question 10

cell-ECM interactions

Answer 10

• anchorage dependent cell growth
• control of cell proliferation/ differentiation in skin epidermis
• also provides cell survival signals- can lead to anoikis
• 90% of cells likely to enter S phase on larger adhesive patch

Question 11

cell-cell interactions

Answer 11

• cell density dependent growth inhibition

- contact inhibition-wound repair

Question 12

maintenance of tissue org:role of ECM/ adhesion

Answer 12

-some tissues, permanent cells- nerve/ cardiac cells live as long as organism
others:
1. replication by simple duplication-live
2. regeneration from undifferentiated cells- replace differentiated cells that cannot divide- common in tissues with high turnover
-cell adhesion to ECM, not just structural but can control cell fate

Question 13

skin epidermis

Answer 13

1. stem cells attached to basal lamina, continue to divide, anchorage dependence
2. decrease in integrins- decrease focal adhesions and hemi-desmosomes
3. detached cells- stop proliferation and drive differentiation
4. increase in cadherins/keratins- increase desmosomes
5. provides strength/ barrier characteristics of skin
6. cells die/flatten-continue to perform necessary function of barrier/ strength
7. sloughed off and replaced- cycle takes 2-4 weeks
   * tumors occur when you lose anchorage dependence

Question 14

growth factor and adhesion signaling cascades

Answer 14

• cell adhesion stimulates convergent pathways
• balance of stim and inhib signals
• kinase vs phosphatases
• GEFs vs GAPs

Question 15

what is different in cancer cells?

Answer 15

• do not senesce (active telomerase or inactive p53)
• lack GF dependence
• lack anchorage dependence
• no cell/cell contact inhibition
• most cancers result from mutations affecting the function of proteins involved in important growth regulatory signal transduction pathways
• oncogenes and tumor suppressor genes

Question 16

oncogene

Answer 16

• mutated or overexpressed versions of genes normally found in genomes
• normal genes called proto-oncogenes
• first discovered in retroviruses- viral oncogenes
• Src- non receptor tyrosine kinase is transforming agent carried by rous sarcoma virus
• viruses account for only 15% of human cancers
• genetic and environmental factors are more important
• conversion from proto-oncogene is usually result of somatic mutations/ not inherited

Question 17

proto-oncogenes

Answer 17

• important proteins at all levels of growth control pathways
• MAPK
• conversion results in elevated/unregulated activity
• mutation of a single allele can cause abnormal growth
• deletion/ pt mutation, gene amp, chromosome rearrangement
• hyperactive protein made in normal amts
• normal protein over produced
• enhancer
• fusion protein
• pp60Scr
• BCR-ABL

Question 18

tumor suppressor genes

Answer 18

• retinoblastoma and p53
• genes normally found in genomes
• normally function to oppose the activity of proto-oncogenes- inhibit growth
• cells lose growth control because these genes are mutated and inactive
• both alleles must be mutated or deleted
• loss of heterozygosity
• first is often inherited

Question 19

retinoblastoma

Answer 19

• negative reg of gene transcription
• in normal cells, blocks transcription
• P on Rb by active cdk inactivates Rb
• release of TF E2F family from RB and permits transcription at G1/S transition
• loss of Rb leads to unregulated transcription

Question 20

p53

Answer 20

• prevents damaged DNA from being replicated
• induces synthesis of a G1 cdk inhibitor (p21)
• blocks Rb phosphorylation
• may induce apoptosis/ senescence
• mutated or missing- damaged DNA will be replicated
• increases probability that new mutations will be seen in progeny
• chromosomes lacking telomeres which can then fuse and fragment- causing gene duplication or loss
• very common in human cancers
• 50% of all cancers
• 75% of colorectal cancers

Question 21

DNA virus proteins

Answer 21

• sequester Rb and p53
• DNA viruses carry proteins that block Rb and p53 leading to hyperproliferation/ transformation of infected cells
• turn on transcription machinery to assist in viral replication
• SV40 virus produces large T antigen protein which binds Rb and p53 and blocks their function
• HPV functions in a similar way (prodices E6 and E7 proteins)
• second biggest cause of female cancer mortality worldwide

Question 22

stages in cancer progression

Answer 22

• loss of cell division/growth control- tumor
• ability to invade and metastasize- malignant tumor- cancer
• transition often occurs in several stages, each marked by a new mutation in a different oncogene or tumor suppressor gene

Question 23

series of mutations and colon cancer

Answer 23

• transformation is the result of 7 mutations
• 3 tumor suppressor genes (2 mutations each)
• 1 proto- oncogene (1 mutation)
• each tumor has distinct genetic profile- can tailor drug therapy to individual