Lect: Growth Control Flashcards
most cells require survival signals to stay alive. When they do not get that signal to stay alive (trophic signals) cells
activate a suicide —apoptosis
With apoptosis you don’t get inflammation.
Cells undergoing necrosis will swell and burst
In the absence of trophic signals, Bad (pro-apoptotic) interacts with Bcl 2 and Bcl10 which are membrane proteins
When Bad interacts with them it blocks their inhibitory interaction with Bax, permitting the formation of a functional Bax containing ion channel and the release of cytochrome C from the mitochndria into the cytosol
When cytochrome c is released, it results in the activation of a series of caspases (serine proteases). this generates a proteolytic amplification cascade.
The caspases digest the cell from the inside out.
Terminal differentiation
cells stop diving after a preset number of divisions and take on a differentiated phenotype
Senescence
after every cell division the ends of the DNA gets smaller but telomerase it adds the six base repeat GGGTTTA onto the ends of the parent DNA strand. Some cancer cells reactivate telomerase and continuing to divide and form a tumor. So they don’t get shorter.
What stage of the cell cycle does p53 blocks entry into when there is DNA damage?
S-phase
If p53 is not working
there would be unstable chromosomes that form from fusions and abnormal recomnbination/breakage. Replication would be deleterious as growth regulatory genes may be inadvertently duplicated, damaged or lost.
External Influences: Growth Factors
diffusible signaling molecules which tell the cell to grow. Some act locally, PDGF only works on platelets while others work long-range (EPO).
External Influences: Adhesions/Substrate
cells show adhesion dependence. Normal cells don;t divide if they don’t get interaction with an insoluble matrix (basement membrane). They need to be anchored
External Influences: cell-cell contact
when they come into contact with their neighbors they stop dividing
Cell adhesion to the basal lamina in the maintenance of tissue organization
need to upregulate intermediate filaments such as keratins.
The undifferentiated stem cells are attached to the basal lamina via integrins (forming hemi-desmosomes and focal adhesions. More adhesions to the basal lamina, more proliferative potential. This is called anchorage dependent cell growth
As the cell differentiates, they express large amounts of intermediate filaments of the keratin family that are involved in the formation of multiple desmosomes between adjacent cells.
This contributes STRENGTH /Barrier of the skin cells. They eventually flatten and are sloughed off to be replaced.
Dysregulation of this process contributes to tumor formation and progression
signaling cascades
proliferation in response to external stimuli involves activation of receptors and integrins (adhesion/ECM receptors), and a cascade of second messengers. This leads to increased transcription of early response genes in the nucleus. They are transcription factors that regulate delayed response genes, including CDKs and cyclins thereby regulating G1/S cell cycle transition.
Normal cells maintain a homeostatic balance of stimulating and inhibiting signals
Oncogenes, Tumor Suppressor Genes and growth control
cancer cells do not respons to the normal cell division signals. They usually lack growth factor dependence, anchorage dependence (cells will grow in suspension), cell-cell contact inhibition (cells grow on top of each other) and do not become senescent. Cancer cells have proteins that have altered activity of the proteins that constitute the growth regulatory signaling pathways
Proto-oncogenes normally stimulate growth and division
Abnormal regulation of cell growth usually results from either a mutation in the protoconcogene leading to hyperactivity or constituitively active product or from a defect in the regulation of proto-onco gene expression (i.e. more proteins then usual due to duplication).
==>needs only one allele of a proto-oncogene to be mutated to affect cell growth
Three ways to convert a proto-oncogene to an oncogene
- deletion or point mutation in coding sequence—>HYPERACTIVE protein made in normal amounts
- gene amplification—> normal protein greatly overproduced
- chromosome rearrangement —>nearby strong ENHANCERrcauses normal protein to be OVEREXPRESSED
- chromosomal rearrangement—> fusion to actively transcribed gene greatly overproduces fusion protein or hyperactive protein
Examples of oncogenic ocnversion: src non-receptor tyrosine kinase
mutation of the phosphorylation site involved in negative regulation of the kinase activity gives rise to a CONSTITUITIVELY ACTIVE knase
Examples of oncogenic ocnversion: ABL tyrosine kinase
translocation os the bcr/abl fusion protein that has constituitive kinase activity.
Tumor Suppressors (Rb, p53, DCC) usually inhibit cell growth
both alleles must be inactivated before uncontrolled growth occurs——-> loss of heterozygosity at the suppressor gene locus
553—halts progression through cell cycle if there is DNA damage. If it is missing or mutated, cells with damaged DNA will divide, increasing the probability that new mutations will arise
DNA viruses and tumor suppressor function
DNA viruses can interfere with Rb and p53 function by utlizing the host cells to produce proteins normally encoded by the viral genome that bind to and sequester Rb and p53 thereby promoting uncontrolled proliferation and tumor formation. Some examples include papilloma virus (cervical cancer)
how does the papilloma virus cause cancer
it produces E6 and E7 that binds and sequester Rb and p53 respectively.
SV40 virus
produces large T-antigen which binds both Rb and p53. Thus these viral proteins can function as oncogenes
Stages in cancer progression
loss of cell division contol leads to formation of a tumor or neoplasm which is benign. The added ability to invade surrounding tissues leads to malignant tumor or cancer. This is accomplished by a down-regulation of cell-cell adhesion molecules and th eproduction of proteolytic enzymes such as metalloproteases that degrade the ECM allowing translocation across the basal lamina and into the blood. This can result in tumor metastasis—the formation of secondary tumors in other organs frequently the lethal step.
