Flashcards in Unit 7 - Growth Control Deck (29):
what three factors control cell division?
1. internal mechanisms (cell lineage)
2. external/diffusible substances
3. cell-cell and cell-ECM interactions
what are 3 examples of apoptosis in fetal development?
2. epithelial cells in palate function
3. up to 80% of neurons in developing brain
what are 2 examples of apoptosis in adults?
1. lining of gut
2. mammary tissue post-lactation (due to hormone deprivation)
what happens to cells in absence of trophic factors? what are some specific factors?
initiate either suicide (apoptosis) or murder (immune system) program
-pro-apoptotic factor Bad interacts with anti-apoptotic PRO BCL2 and BCLX in mitochondrial membrane
--BCL2/X inhibition on Bax is inhibited itself, so Bax is active
-Bax has ion channels and releases cytochrome C from mitochondria into cytosol
-caspases (cysteine proteases) are activated via caspase-dependent proteolytic cleavage from procaspases, to digest intracellular PRO like nuclear lamins
--generates proteolytic amplification cascade
difference between apoptosis and necrosis?
apoptosis: cells srhink, condense, and fragment, releasing small membrane-bound apoptotic bodies that are phagocytosed
-intracellular contents are not released into ECM, so no deleterious effects on neighboring cells, or inflammation
necrosis: cells swell and burst, releasing intracellular contents and frequently cause inflammation
what is terminal differentiation?
cells stop dividing after a pre-set number of divisions, and take on a differentiated phenotype
what is senescence?
thought to result from running out of telomeres
what is an important ribozyme in senecense? what happens to this ribozyme in cancer?
ribozymes are part PRO, part RNA
-telomerase is most important, adding GGGTTA on end of parental DNA strand
--some cancers reactivate this, avoiding senescence, and continuing division
what happens when telomeres are too short?
1. activate p53
2. p21 CDK inhibition blocks cells in G1
3. senescence occurs
what are the effects of growth factors?
these diffusible signaling molecules can have concentration and cell-type specific effects
-can act locally (like PDGF released from platelets to stimulate wound healing) or systemically (like EPO for RBC differentiation)
what is cell-ECM (cell-substrate) interaction?
adhesion-dependence (anchorage-dependent cell growth) and cell-survival signals
-normal cells fail to divide if deprived of interaction with insoluble matrix
-there's no apoptosis, but instead anoikis
what kind of cell interaction does stratified epithelia exemplify?
cell-substrate (cell-ECM) interaction
-regulates cell proliferation, b/c only the cells in direct contact with basal lamina continue to divide
-cells in suprabasal layer stop proliferating, and instead differentiate
density-dependent growth inhibition (cell-cell contact inhibition)
-observed during wound repair
what is the role of cell adhesion to basal lamina in maintenance of tissue organization?
overall organization and maintenance of tissue needs tightly regulated modification of cell adhesion characteristics and changes in gene expression of structural proteins (like intermediate filament keratins)
how are basal cells attached to basal lamina?
anchorage-dependent cell growth via members of integrin family (form hemi-desmosomes and focal adhesions) that critically influences cell fate
-cells with the highest number of receptors, and adhering the most tightly, have greater proliferative potential
what happens if there is loss of surface expression of integrins on stem cells?
ejection of basal cells from basal layer
-confirm decision to differentiate, and loss of proliferative potential
-during differentiation, they express large amounts of intermediate filaments of keratin family involved in formation of multiple desmosomes between adjacent cells (contributes to strength of skin)
-eventually, keratinocytes lose nuclei, are flattened, and sloughed off
-entire thing is 2-4 week process
what are signaling cascades?
proliferation in response to external stimuli involves activation of receptors (growth factor receptors, adhesion/ECM receptors) and cascade of second messengers (MAPK)
-leads to increased transcription of early response genes in nucleus
normal cells maintain homeostatic balance of stimulating and inhibiting signals
how are cancer cells different from normally dividing cells?
1. lack growth factor dependence
2. lack anchorage dependence (cells grow in suspension or soft agar)
3. lack cell-cell contact inhibition (cells grow on top of each other, forming foci)
4. don't become senescent (may be due to active telomerase, or inactive p53)
what are proto-oncogenes? oncogenes?
PO: encode normal cellular proteins that function to stimulate cell growth and division
-include growth factors, growth factor receptors, tyrosine-specific PRO kinases, and transcription-regulating PRO
O: mutated form of PO, that is hyper-active or constitutively active
-or could be defect in regulation of PO expression
how many alleles of a proto-oncogene need to be mutated to affect cell growth?
only one allele
what are 2 examples of oncogenicc conversion?
1. Src non-receptor tyrosine kinase
-mutation of phosphorylation site involved in negative regulation of tyrosine kinase gives rise to constitutively active kinase
2. Abl tyrosine kinase
-abnormal translocation of Xm 22 and 0 cause hybrid gene encoding BCR-ABL fusion PRO with constitutive kinase activity
-cause of CML
how are oncogenes related to retroviruses?
many oncogenes were first found in retroviruses (v-one)
-many plant and animal tumors are caused by viruses (v-src oncogene of Rous sarcoma virus causes sarcomas in chickens)
-not so many human cancers (15%)
what are tumor suppressor genes? examples? how many alleles need to be inactivated?
encode factors that normally function to inhibit cell growth
-include Rb (retinoblastoma), p53, and DCC (deleted in colorectal carcinoma)
-both alleles need to be inactivated (mutated or deleted), and usually seen as Loss of Heterozygosity (LOH) at suppressor gene locus
--means first mutation/deletion is usually inherited, and these people are predisposed to cancer
what is Rb?
reinoblastoma tumor suppressor gene
-inhibits gene transcription
-is controlled by CDK
-in active, non-phosphorylated state, Rb binds and sequesters transcription factor E2F
-phosphorylation by CDK inactivates it, leading to conformation change and release of E2F, allowing transcription to proceed
-loss of Rb through mutation events lead to constitutive transcription, and uncontrolled growth/transformation
what is the p53 tumor suppressor protein important for?
checkpoint control of DNA damage
-if DNA is damaged, p53 halts progression through cell cycle by inducing synthesis of p21 (G1/S CDK inhibitor that prevents Rb phsophorylation) and induces apoptosis
-if p53 is mutated/missing, cells with damaged DNA can divide, inducing new mutations (50% in cancer, 75% of colorectal cancers)
how are DNA viruses and tumor suppressor function related?
DNA viruses interfere with Rb and p53 function by utilizing host cells to produce PRO normally encoded by viral genome, that bind to and sequester Rb and p53, thus promoting uncontrolled proliferation and tumor formation
how are papilloma and SV40 viruses related to cancer?
P: produces PRO E6/7 that bind and sequester Rb and p53, respectively
SV: makes large T antigen, that binds both Rb and p53
so both can function as oncogenes
what are the stages in cancer progression?
1. loss of cell division control leads to formation of a benign tumor or neoplasm
2. added ability to invade surrounding tissues (frequently accompanied by loss of differentiated phenotype) leads to malignant tumor/cancer
-accomplished by down-regulation of cell-cell adhesion molecules and production of proteolytic enzymes (metallo- and serine proteases that degrade ECM), allowing translocation across basal lamina and into blood stream
3. tumor metastasis (formation of secondary tumors in other organs) is usually lethal step