MCM 2-13 Growth Control

Question 1

internal factors that regulate growth control

Answer 1

apoptosis, terminal differentiation, senescence

Question 2

apoptosis

Answer 2

programmed cell death

occurs during normal development (formation of digits, etc.)

most cells require trophic factors to stay alive, in absense of these signals, cells initiate apoptotic pathway

• signaling cascade = activation of cystein proteases called caspaces from procaspase forms
• these digest important intracellular structural proteins like lamin and cytoskeletal proteins.

Question 3

what happens to cells when they apoptose?

Answer 3

apoptotic cells shrink and fragment, releasing small, membrane bound apoptotic bodies that are phagocytized by macrophages.
-This controlled waste disposal prevents cytosolic contents from leaking into the EC space which would cause inflammation (this happens in necrotic cells)

Question 4

terminal differentiation

Answer 4

process by which the specific gene upregulatory proteins of certain differentiated cells (neuron, cardiac muscle cells) prevent the cells from dividing further. Significant barrier to recovery from spinal and cardiac injuries.

Question 5

Senescence

Answer 5

process by which cells of a given cell line stop dividing

due to absence of telomerase (an enzyme with an RNA portion used to add six-base repeats to telomeres)

-allows for complete syntehsis of the lagging strand in DNA replication

when telomeres get too short, p53 activated, leading to senescence. This limits unwanted proliferation and prevents replication of incomplete and unstable chromosomes.

Most adult tissues lake telomerase

Question 6

external factors that regulate growth control

Answer 6

Growth factors, Cell ahdesion (Cell-EM interactions and Cell-cell interactions)

Question 7

Growth factors

Answer 7

chemical messengers that influence cell growth. They are concentration and cell-type specific.

They can act locally (PDGF released by platelets to stimulate wound repair)

or systemically (erythropoetin produced by kidney to stimulate red blood cell differentiation in bone marrow)

Question 8

Cell Adhesion

Answer 8

Cell-ECM interactions - anchorage dependant cell growth. ADhesion to the ECM stimulates cells to proliferate. Interactions via folal adhesions stimulate convergent pathways.

Cell-Cell Interactions - contact inhibition. Serve as negative regulator of cell proliferation (wound repair)

Question 9

how do normal cellular genes become oncogenic?

Answer 9

normal cellular genes with potential to become oncogenic are called proto-oncogenes.

protooncogense have important normal cellular functions: stimulate cell growth and/or proliferation.

conversion to oncogene results in elevation/unregulated activity

a mutuation in even a single allele of proto-oncogene can cause abnormal growth/differentiation.

Question 10

proto-oncogene mutations are ________ and of what types?

Answer 10

proto-oncogene mutations are somatic and of the following types

deletions or point mutations in the coding sequence - leads to production of hyperactive protein in normal amounts

gene amplification - leads to normal protein being overproduced

chromosome rearrangement - when gene is moved into the vicinity of a strong enhancer, normal protein is overproduced
when the gene is fused to an actively transcribed gene, a fusion protein is either produced in large amounts, or is simply hyperactive

Question 11

how tumor suppressor genes regulate growth

Answer 11

TSG’s generally function to inhibit growth by opposing activity of proto-oncogenes.

both alleles of TSG must be lost before uncontrolled growth will occur (loss of heterozygosity)

cancer-predisposing genotypes related to tumor suppressor genes are inherited. - one can inherit a single bad tumor suppressor allele and be more likely to develop cancer due to a somatic loss of the other tumor suppressors alleles function.

Question 12

why do most cancers involve cumulative mutations?

Answer 12

cells undergoing uncontrolled growth will form tumors.
once they obtain the ability to invade other tissues and metastasize, they form malignant tumors and have become cancer cells.

the transition between these two states typically occurs in steps, each marked by a new mutatiion in a different proto-oncogene or TSG.

because of this mutation profile that develops, oncotherapies are best tailored to the individual

Question 13

3 types of factors that regulate growth control

Answer 13

1. cell lineage (internal)
2. external/diffusable factors (growth hormones)
3. cell/cell and cell/ECM adhesion interactions

Question 14

describe cell lineage control of cell growth

Answer 14

internal control of G1/S transition

apoptosis - carefully controlled waste disposal

also occurs in normal development (digitization and neuronal connection trimming)

• occurs in normal adult cells (lining of gut, mammary tissue post lactation)
• also occurs as a result of checkpoint error during DNA replication cycle

Question 15

improper apoptosis during digitization

Answer 15

syndactyly

Question 16

what causes neuronal cell apoptosis

Answer 16

during development, absense of trophic factors (survival factors) excreted by target cells

cell death balances the number of neurons to number of target cells

Question 17

describe apoptotic cells

Answer 17

cells shrink, form membrane blebs that fragment, releasing small membrane bound apoptotic bodies that are phagocytized by macrophages

-prevents inflammation

as opposed to necrotic cells that swell, burst, and cause huge inflammation

Question 18

describe a neuron that is receiving enough trophic factors vs one that is not

Answer 18

receving enough trophic factors - initiates signaling cascade that causes pro-apoptotic factor BAD to get sequestered in cytosol. cell survives.

not receiving enough - BAD remains active, interacts with anti-apoptotic proteins in mitochondria.
End result = inhibitory role on BAD is lost, ions enter mitochondria. cytochrome c released. this gives rise to a catalytic cascade, which causes the internal degredation and apoptotic bodies start to form and get released.

Question 19

Terminal Differentiation

Answer 19

Second internal mechaism of G1/S transition control

some cells stop dividing (express a novel set of genes for the specialized function of cell)

ex) neurons and cardiac muscle cells

causes barrier to spine injury and heart disease treatments

Question 20

Senescence

Answer 20

Third mechanism of internal control of G1/S transition

cells in culture will stop dividing after 50-100 divisions due to absence of enzyme called telomerase

this causes the telomeres to shorter with each round of replication, signaling pathways (including p53 upregulated which upregulates p21 CDK inhibitor, blocks cells in G1

important for limiting unwanted differentiation

Question 21

telomerase

Answer 21

an enzyme, more specifically a ribozyme (half protein, half RNA)
-adds 6 base pair noncoding repeats to ends of chromosomes (parental)

allows for more complete syntehsis

Question 22

most ______ cells lack telomerase

Answer 22

somatic cells

Question 23

growth factors

Answer 23

a type of external factor influencing cell cycle movement

-some act locally (PDGF) some act distantly (erythropoietin)

Question 24

Cell-ECM interactions

Answer 24

a type of external factor influencing differentiation/cell cycle/growth

“anchorage dependent cell growth” e.g. control of cell proliferation/differentation at the skin epidermis

healthy cells that are suspended will not proliferate, must be given patch to adhere to.

cells allowed to adhere to small amounts of ECM protein (fibronectin, collagen) will form a few focal adhesions and some will proliferate

Cell adhesion to ECM can induce proliferation

Question 25

cell-cell interactions

Answer 25

cell density dependant growth inhibition = contact inhibition (important in wound repair)

Question 26

cell adhesion to ECM, not just structural but can also control

Answer 26

cell fate

Question 27

describe skin epidermis example

Answer 27

skin epidermis is hostile, constantly sloughing off

only cells in contact with basal lamina can undergo cell division - they are experiencing anchorage-dependent cell growth/differentiation

when these cells escape, integrins get downregulated, and will start differentiating into skin cells and upregulate adherins and IF to form cell:cell desmosomes that are important for the barrier function of skin

process goes awry - tumors

Question 28

growth control is a balance between

Answer 28

stimulatory and inhibitory signals (kinase vs phosphatases) (GEFs vs GAPS)

example is MAP kinase pathway - cascade of various kinase signaling molecules activate downstream kinases that activate downstream molecules

when kinases activate they are a phosphorylated intermediate

phosphatases can dephosphorylate, causing deactivation

RAS is activtated by GEF, inhibited by GAS. balance of GEF and GAS determines if pathway is activated

Question 29

characteristics that cancer cells may or may not exhibit

Answer 29

do not senesce (active telomerase or inactive p53)

lack growth factor dependence

lack anchorage dependence (will grow in suspension )

no-cell:cell contact inhibition (cells will pile up on top of each other and form Foci)

Question 30

most cancers result from

Answer 30

mutations affecting the function of proteins involved in important regulatory signal transduction pathways

2 main classes - oncogenes and tumor supressor genes

Question 31

Oncogenes

example?

Answer 31

mutated/overexpress versions of genes normally found in cellular genomes (proto-oncogenes)

HER2 and HER2B

Generally the result of somatic mutation (not inherited - would cause inviable fetus)

-they normally stimulate growth/cell proliferation, their mutation causes elevated or unregulated activity

mutation of single allele is enough to cause abnormal growth

Question 32

what causes the HER2 mutation?

Answer 32

upregulation of expression of cell surface receptor

Question 33

tumor supressor genes

Answer 33

normally found in genomes to oppose activity of proto-oncogenes

Retinoblastoma and P53

both alleles must be mutated, those who inherit iare more susecptible due to only needing a single mutation.

ex) (BRCA1/BRCA2)

mutations in tumor supressors makes them an inactive form

Question 34

Retinoblastoma

Answer 34

tumor suppressor cell
-the active Rb sequesters transcription factors like eFII.

Phosphorylation by CDK causes the release of TF factors and transcription of the target gene (permits G1-> S transition)

loss of retinoblastoma function - unregulated transcription

p53 can upregulate p21, which inhibits CDK which can no longer phosphorylate Rb to release the Transcription factors

Question 35

p53

Answer 35

Tumor supressor, prevents damaged DNA from being replicated.

-normally upregulates p21 which blocks the G1 CDK, which prevents Rb from getting phosphorylated, keeps TF locked down

Mutated/damaged p53 = damaged DNA gets replicated.

increases possibility that new mutations will be “Seen” in progeny

damaged DNA can be replicated - chromosomes lacking telomerase can then fuse/fragment causing gene duplication or loss

p53 mutations are common in cancer
50% of all
75% colorectal

Question 36

How do DNA viruses cause cancer?

Answer 36

DNA viruses carry genes the encode proteins to block Rb andp53 function, leading to hyperproliferation and transformation of infected cells = turn on cell transcription machinery to assist in replication

Question 37

SV40 Virus

Answer 37

encodes large T antigen which binds Rb and p53, blocking their function

Question 38

HPV

Answer 38

produces two proteins (e6 and e7) which bind p53 and Rb, respectively.

Question 39

stages in cancer progression

Answer 39

1. loss of cell division/growth control leads to a tumor
2. mutations within the tumor that eventually allow cells to break off and metastasize form widespread malignant tumors leading to cancer

transition occurs in multiple stages, each marked by a new mutation in a different oncogene or tumor suppressor gene

Question 40

each tumor has a unique

Answer 40

genetic profile, allowing for tailored treatment options

Question 41

the kinase that phosphorylates the Rb protein, allowing E2F dependent transcription can best be described as a

Answer 41

proto-oncogene