1. Cell division (cell number)
2. Cell death
3. Cell growth
Organism size is determined by what three factors?
Intracellular and extracellular events/molecules
Cell division, cell death and cell growth are controlled by what?
2. Growth factors
3. Survival factors
Extracellular molecules are soluble factors that are grouped into what three categories?
What are extracellular signals (stimulatory molecules) released from neighboring cells that stimulate cellular proliferation?
Platelet-Derived Growth Factor (PDGF)
What was the first mitogen identified?
What are anucleated cells that circulate in the blood and help stimulate blood clotting at sites of tissue injury?
Platelets release factors that promote cell division for what?
2. Smooth muscle cells
3. Neuroglial cells
PDGF is a protein that acts as a mitogen for a broad range of cells including what cells?
Cell growth, survival, differentiation and migration
PDGF stimulates what?
Epidermal growth factor
What growth factor (EGF) which acts on epidermal and epithelial cells to stimulate cell division?
What mitogen is involved in stimulating division of red blood cell precursors?
What is the non dividing state in the cell cycle where cells exit from the cell cycle?
Most of the cells in our body are in what state in the cell cycle where the cell cycle machinery is partially diassembled?
Terminally differentiated G0
The cell cycle machinery is dismantled and cell division rarely occurs in what state in the cell cycle?
What stimulates cell growth by promoting protein synthesis?
What promotes cell survival by suppressing cell death?
Mitogens control the rate of cell division by acting in the G1 phase of the cell cycle to promote entry into what phase?
An intracellular kinase signalling cascade
Mitogens bind to cell surface receptors triggering what?
One major pathway, acting through the Ras GTPase, leads to the upregulation of what gene regulatory protein?
Myc acts to increase the expression of G1 cyclins to increase what activity?
Increasing cell growth
Myc also upregulates the expression of genes responsible for
The purpose of G1-CDK is to activate gene regulatory factors like what?
1. G1/S cyclins
2. S cyclins
3. Proteins involved in DNA synthesis and chromosome segregation
E2F binds to the promoter region of genes that encode proteins necessary for S-phase entry including what?
Retinoblastoma protein (Rb) and is inactive
In the absence of mitogen activation, E2F is complexed with what? Is it active or inactive?
With mitogen activation, G1-Cdk phosphorylates Rb decreasing its affinity for what?
Released E2F activates transcription of target genes to promote entry into what phase?
A positive feedback loop increasing E2F activity
One of the genes activated by E2F, is E2F itself, generating what kind of feedback loop? Does it increase or decrease E2F activity?
Prevent entry into S phase and progression through the G2/M checkpoint
Intracellular and extracellular agents that induce DNA damage can do what to the cell cycle?
DNA damage activates what pair of protein kinases?
Chk1 and Chk2
Knases (ATM/ATR) phosphorylate and activate what two kinases?
Chk1/Chk2 phosphorylate target proteins including what gene regulatory protein?
Phosphorylated p53 has reduced affinity for what ubiquitin ligase?
Active and stable p53 protein
Phosphorylated p53 has reduced affinity for the ubiquitin ligase Mdm2. This leads to an accumulation of what?
Active p53 activates the transcription of what CKI protein?
Cdc25 phosphatase inhibiting its activity
Chk1 and Chk2 kinases also phosphorylates what? Does it increase or decrease its activity?
1. Induce phosphorylation of the ubiquitin ligase, Mdm2
2. Induce a decrease in Mdm2 protein production
DNA damage can result in what two results (with Mdm2)?
An increase in p53 protein amplifying p21 expression and G1/S-CDK and S/Cdk inactvation
Either the phosphorylation of Mdm2 or the decrease in Mdm2 protein production leads to what?
What binds to G1/S-Cdk and S-Cdk inhibiting their activities and blocking entry into the cell cycle?
Accumulation of genetic damage in cells that lack a functional DNA response system leads to increased frequency of what?
Half of all human cancers are linked to mutations in what gene?
A rare genetic disease in which patients are very sensitive to X-rays have mutations in the what gene?
Cells that accumulate severe DNA damage typically undergo what?
Mutations in several of the components of the mitogen signaling pathway have been linked to what?
Mutations identified as promoting cancer are called what?
Ras and Myc
Mutations identified as promoting cancer are called 'oncogenes' and include what small GTPases?
Mutations that generate what form of the protein that stimulates excessive cell growth and proliferation in the absence of a mitogenic signal?
A cell cycle inhibitor protein, ARF (alternate reading frame)
Upon detection of excessive mitogenic stimulation, levels of what is increased?
Arf binds to, and inhibits, the activity of what?
Mdm2 ubiquitinates what promoting its degradation?
When Mdm2 is sequestered by Arf, the levels of what increase?
1. Cell cycle arrest
2. Cellular apoptosis
The increase in p53 leads to what two outcomes?
p53 and/or Arf
This safety mechanism is often inactivated in cancer cells by mutations in what?
For growth, increased cell proliferation must be accompanied by what?
Increased cell mass is dependent on extracellular signaling molecules called what?
An intracellular signalling cascade
Growth factors bind to cell surface receptors triggering the activation of what?
The intracellular signalling cascade increases the rate of protein synthesis while decreasing what?
Nutrient uptake and ATP synthesis
What are elevated during cellular growth?
A major pathway activated by growth factors involves what kinase?
PI3 kinase converts PIP2 to what?
The Tor kinase
PI3 kinase converts PIP2 to PIP3 which activates what?
Protein synthesis and cell growth
Tor kinase activates targets which stimulate what?
Cell growth and cell division
To maintain a constant cell size, what must be coordinated?
Growth and division are not coupled events for all cell types; but is coupled in what kind of cells?
Which pathway's rate of cell division is controlled by cell growth with division occuring only after a cell has reached a minimum size?
Which pathway has factors can control both growth and division simultaneously?
Which pathway's cells growth and division are under the control of separate factors but it is the relative amount of each controlling factor that dictates division relative to growth?
Actual cell number
For all organisms, it is the final total cell mass, not what, that controls cellular division
Salamanders of varying ploidy have a cell size that correlates with what?
Their total number of cells differ
Salamanders are the same size but what differs?
The total cell mass
Although the haploid organism has 5X the number of cells as the pentaploid organism, what does not differ between the organisms?
There is a mechanism in place that measures what and not cell number when determining cell growth and division cycles?