Cell Cycle Regulation

What are cells that are often renewed inside the organism?

epithelial cells that line the outer surfaces and innter cavities of the body

What are cells that preserve that capability to divide but only do so in specific cases?

liver cells, or white blood cells will leave their resting state and start dividing

What are cells that have lost this ability after they have obtained their differentiated form and remain like this until they die?

neurons and muscle cells

What does the M/G1 checkppint check for?

chromosome arrangement at metaphase plate

What does the G1/S checkpoint check for?

cell size, nutrients and energy, DNA damage, growth factors

What does the G2/M checkpoint check for?

DNA damage, completion of DNA replication

When does each cyclin increase in concentration?

when it is needed

What do different cyclins drive?

different Cdks to specific targets that are essential for each stage

What does the ORC remain associated with throughout the cell cycle?

the ori

What do Cdc6 and Cdt1 do in G1?

associate with the ORC and the resulting complex allows the assembly of the MCM ring and the formation of the prereplication complex

What does cyclin A-Cdk (S-Cdk) do?

helps prevent re-replication by promoting the degradation of Cdc6 and inhibition of Cdt1 through phosphorylation-dependent ubiquitination

What promotes the accumulation of geminin?

cycling A-Cdk

When is the cell able to reassemble the pre-RC?

only after the mitotic cyclin (B-Cdk) is destroyed at the end of the M-phase

What is the first way S-Cdk prevents re-replication?

destroys licensing factors Cdc6 and Cdt1

How does S-Cdk destroy Cdc6?

S-Cdk phosphorylates Cdc6, targets it for ubiquitin mediated degradation

What is Cdt1 inhibited by?

geminin, which accumulates during S phase and binds to Cdt1, preventing it from loading MCM helicases

How also happens to Cdt1 is some contexts?

it is degraded in response to replication

What is the second way S-Cdk prevents re-replication?

prevents new pre-replication assembly?

How does S-Cdk prevent new pre-replication complex assembly?

S-Cdk phosphorylates ORC and MCM components, inhibiting their ability to reload the helicase onto origins

What can new replication origins cannot be licensed without?

Cdc6, Cdt1, and active ORC/MCM

What is the third wat S-Cdk prevents re-replication?

maintains inhibition through G2 and early mitosis

What happens as long as S-Cdk and M-Cdk are active?

origin licensing is blocked

When can pre-RCs form again for the next cycle?

only in late mitosis/early G1, when Cdk activity drops

What are the FUCCI Cells cycles of destruction?

licensing, firing of origins, termination of replication

What is licensing?

begins with removal of geminin and resetting of Cdt1 to establish pre-replication complexes

What is firing of origins?

initiates destruction of Cdt1 and stabilization of geminin to ensure re-replication does not occur

What is termination of replications (FUCCI cells)?

targeting the destruction of geminin releases Cdt1 from inhibition so that reestablishment of pre-replication complexes can happen quickly if needed

What are cyclin/Cdk complexes regulated by?

transcription, protein modification, destruction

What is Whi5?

a transcriptional regulator in yeast

What is SBF?

a transcription factor complex composed of two proteins: Swi4 and Swi6

What does Cln3 equal?

G1 cyclin

What does Cln1/2 equal?

G1/S cyclins

What happens to Cln3 when nutrients are high?

it is translated

What does the G1/Cdk complex do to Whi5?

it phosphorylates

What does the phosphorylation of Whi5 do?

sets SBF free and transcription of G1/S cyclins start

What accumulates in response to growth factors in mammals?

G1 cyclin D

What do growth factors/mitogens do?

activate gene transcription

What does Myc do?

activates secondary response genes, such as the G1 cyclin D

What must happen if it is unsafe for a cell to divide?

the transition from one phase to the next must be prevented

What does p53 do?

recruit enzymes that are responsible for repairing the DNA

What does p53 if DNA cannot be repaired/

activates apoptosis

When does p53 function?

in al phase of the cell cycle but more dominant in G1

When does Rb act?

at the G1 phase

What happens to Rb when the cell size is small?

it is not phosphorylated

Why is Rb not phosphorylated when the cell size is small?

it binds to the transcription factor E2F and blocks the transcription, and production of proteins that are necessary for the G1/S transition

What do ATM/ATR kinases do?

phosphorylates Chk1/2 kinases which then phosphorylate p53

What is Mdm2?

an E3 ubiquitin ligase that constantly degrades p53

What does p53 stabilization lead to?

p21 production

What is p21?

a Cdk inhibitor protein

What does binding of p21 to cyclin-cdks do?

blocks progression through the cell cycle and gives time for the cell to decide

What happens once the G1 cyclin is expressed?

the G1 cyclin/Cdk complex phosphorylates Rb

What assures entry into S-phase?

a feedback loop

What does Rb bind to in early G1?

inhibits E2F transcription factors

What is cyclin D-Cdk4/6 activated by in early G1?

growth signals and partially phosphorylates Rb, weakening its hold on E2F

What happens as E2F is partially released?

it begins to transcribe target genes including cyclin E an E2F itself

What is the positive feedback loop for entry into S phase?

E2F to cyclin E to Cdk2

What does cyclin E-Cdk2 further hyperphosphorylate?

Rb, fully releasing E2F

What does fully active E2F do?

drives more cyclin E and E2F expression

What does degrades cell cycle regualtors?

SCF and APC

What is the main driver of anaphase?

anaphase promoting complex/cyclosome (APC/C)

What is the first heritable property cancer cells are defined by?

they do not reproduce in the normal way of cell growth and divisions

What is the second heritable property cancer cells are defined by?

they invade and colonize territories normally reserved for other cells

What do cancer-associated mutations that perturb cell cycle control allow?

continuous cell division chiefly by compromising the ability of cells to exit the cell cycle

What do continuous rounds of division create?

increased reliance on other cell cycle control mechanisms to prevent catastrophic levels of damage and maintain cell visibility

What do cancer cells lose?

contact-inhibition

Why do cancer cells not have contact inhibition?

they have changed the cell adhesion molecules on their surfaces

What is metastases?

cancer cells leaving their home tissues and invading others

What is some cancer cell abnormal morphology?

small cytoplasm, multiple nuclei, multiple and large nucleoli, coarse chromatin

Do cancer cells have normal chromosomal arrangements?

no

What is the warburg effect?

cancer cells tend to favor glycolysis for energy production even in the presence of sufficient oxygen

What advantages does the Warburg effect have on cancer cells?

rapid energy production, acidic environment, oxidative stress reduction

Why is the Warburg effect good for rapid energy production?

glycolysis provides ATP at a faster rate, cancer cells generate intermediates that serve as building blocks for other molecules

Why does the Warburg effect create an acidic environment?

accumulation of lactate, acidification of tumor environment can inhibit immune response

Why does the Warburg effect lead to oxidative stress reduction?

less reliance on oxidative phosphorylation reduce ROS, which can damage cells and help to evade apoptosis

How is the increased glucose uptake by cancer cells exploited?

in PET scans using fluorodeoxyglucose to detect tumors

What is an ongoing area of cancer therapy research?

efforts to disrupt glycolysis or the associated metabolic pathways

How fast do cancer cells grow initially?

slowly, it takes some breast cancer cell 100 days to double

What are carcinomas?

derived from epithelial cells, account for 80% of all cancers

What are benign carcinomas called?

adenomas

What are malignant carcinomas called?

adenocarcinomas

What are sarcomas?

derived from connective tissue or muscle cells

What are benign sarcomas?

chondromas

What are malignant sarcomas?

chondrosarcomas

What are leukemias and lymphomas derived from?

blood cells

What can cancers be caused by?

a variety of viruses, many of which we have immunizations against

What can increase the likelihood of developing cancer?

environmental factors and lifestyle

What is the most important cause for cancer?

genetics

What did sequencing reveal?

commonly mutated genes in cancer patients from all cancer classes

What pathways do 74% of all cancers have mutations in?

Rb, growth factor, p53

What are the 2 types of cancer genes?

proto-oncogenes and tumor suppressor genes

What is a proto-oncogene?

a normal gene that can become an oncogene due to mutations or increased expression

What is an example of an oncogene?

mutations in receptor tyrosine kinases or their signal transducers

What are mechanisms through which oncogenes are generated?

deletion or point mutation in coding sequence, regulatory mutation, gene amplification, chromosome rearrangement

What is an example of a tumor suppressor gene?

retinablastoma protein (Rb)

What can gene functions in cancer be caused by?

mutations in DNA or by epigenetic modifications

What is one of the most extensively studied PTM?

phosphorylation

What does phosphorylation regulate?

a number of cellular functions like cell growth, differentiation, apoptosis, and cell signaling

What do alterations in phosphorylation pathways result in?

serious outcomes in the forms of diseases

What are important tools to investigate cell cycle, cancer, and signaling pathways?

phospho-specific antibodies