Growth Control Flashcards
1
Q
growth control
A
- 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
2
Q
cell lineage
A
- internal control of G1/S transition
- apoptosis- occurs during natural development
- checkpoint error
3
Q
apoptosis during normal development
A
- formation of digits- defect is syndactyly
- epithelial cells during palate fusion
- neurons in developing brain
also occurs in normal adult cells - lining of gut
- mammary tissue post lactation
4
Q
control of neuron number during development
A
- start with more nerve cells than targets
- most cells require signals to stay alive
- others die off via apoptosis
5
Q
morphology
A
- 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
6
Q
signaling and apoptosis-intrinsic pathway
A
- in absence of trophic factors, pro-apoptotic factor Bad can interact with anti-apoptotic proteins BCL2 and Bclcl in outer mito membrane
- this blocks their inhibitory interaction with Bax and permits formation of Bax containing channels and the release of cytochrome c from mito
- results in activation of caspases (from cleavage of procaspases), which generates proteolytic amplification cascade
- caspases digest important intracellular structural proteins such as lamins and cytoskeleltal proteins, leading to demise and fragmentation
7
Q
terminal differentiation
A
- cells stop dividing
- neurons, cardiac cells
- significant barrier to recovery from spinal cord injury or heart disease
- mature cells of skin/ gut
8
Q
senescence
A
- 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
9
Q
growth factors
A
- 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
10
Q
cell-ECM interactions
A
- 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
11
Q
cell-cell interactions
A
- cell density dependent growth inhibition
- contact inhibition-wound repair
12
Q
maintenance of tissue org:role of ECM/ adhesion
A
-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
13
Q
skin epidermis
A
- stem cells attached to basal lamina, continue to divide, anchorage dependence
- decrease in integrins- decrease focal adhesions and hemi-desmosomes
- detached cells- stop proliferation and drive differentiation
- increase in cadherins/keratins- increase desmosomes
- provides strength/ barrier characteristics of skin
- cells die/flatten-continue to perform necessary function of barrier/ strength
- sloughed off and replaced- cycle takes 2-4 weeks
* tumors occur when you lose anchorage dependence
14
Q
growth factor and adhesion signaling cascades
A
- cell adhesion stimulates convergent pathways
- balance of stim and inhib signals
- kinase vs phosphatases
- GEFs vs GAPs
15
Q
what is different in cancer cells?
A
- 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
16
Q
oncogene
A
- 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
17
Q
proto-oncogenes
A
- 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
18
Q
tumor suppressor genes
A
- 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
19
Q
retinoblastoma
A
- 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
20
Q
p53
A
- 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
21
Q
DNA virus proteins
A
- 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
22
Q
stages in cancer progression
A
- 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
23
Q
series of mutations and colon cancer
A
- 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
