Molecular Biology of the Cell Chapter 17 Part 4

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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?

1. Mitogens
2. Growth factors
3. Survival factors

Extracellular molecules are soluble factors that are grouped into what three categories?

Mitogens

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?

Platelets

What are anucleated cells that circulate in the blood and help stimulate blood clotting at sites of tissue injury?

Wound healing

Platelets release factors that promote cell division for what?

1. Fibroblasts
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?

Erythropoietin

What mitogen is involved in stimulating division of red blood cell precursors?

G0

What is the non dividing state in the cell cycle where cells exit from the cell cycle?

G0

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?

Growth factors

What stimulates cell growth by promoting protein synthesis?

Survival factors

What promotes cell survival by suppressing cell death?

S phase

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?

Myc

One major pathway, acting through the Ras GTPase, leads to the upregulation of what gene regulatory protein?

G1-CDK activity

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
what?

E2F

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?

E2F

With mitogen activation, G1-Cdk phosphorylates Rb decreasing its affinity for what?

S-phase

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?

ATM/ATR

DNA damage activates what pair of protein kinases?

Chk1 and Chk2

Knases (ATM/ATR) phosphorylate and activate what two kinases?

p53

Chk1/Chk2 phosphorylate target proteins including what gene regulatory protein?

Mdm2

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?

p21

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?

p21

What binds to G1/S-Cdk and S-Cdk inhibiting their activities and blocking entry into the cell cycle?

Cancer-promoting mutations

Accumulation of genetic damage in cells that lack a functional DNA response system leads to increased frequency of what?

p53

Half of all human cancers are linked to mutations in what gene?

ATM

A rare genetic disease in which patients are very sensitive to X-rays have mutations in the what gene?

Apoptosis

Cells that accumulate severe DNA damage typically undergo what?

Cancer

Mutations in several of the components of the mitogen signaling pathway have been linked to what?

'Oncogenes'

Mutations identified as promoting cancer are called what?

Ras and Myc

Mutations identified as promoting cancer are called 'oncogenes' and include what small GTPases?

'Hyperactive' form

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?

Mdm2

Arf binds to, and inhibits, the activity of what?

p53

Mdm2 ubiquitinates what promoting its degradation?

p53

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?

Cell growth

For growth, increased cell proliferation must be accompanied by what?

Growth factors

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?

Protein degradation

The intracellular signalling cascade increases the rate of protein synthesis while decreasing what?

Nutrient uptake and ATP synthesis

What are elevated during cellular growth?

PI3 kinase

A major pathway activated by growth factors involves what kinase?

PIP3

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?

Proliferating cells

Growth and division are not coupled events for all cell types; but is coupled in what kind of cells?

Pathway A

Which pathway's rate of cell division is controlled by cell growth with division occuring only after a cell has reached a minimum size?

Pathway C

Which pathway has factors can control both growth and division simultaneously?

Pathway B

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

Genome content

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?

Cell mass

There is a mechanism in place that measures what and not cell number when determining cell growth and division cycles?

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