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SFM EXAM 2a/b 2020 > Cell Cycle, Cancer, and Cell death > Flashcards

Cell Cycle, Cancer, and Cell death Flashcards

1
Q

reference reading and LO #1 Cell Cycle, Cancer, and Cell death

A

REFERENCE READING: References and citations for further reviewing and reading: • Lippincott’s Illustrated Reviews: Cell and Molecular Biology, 2e. 2019. Nalini Chandar and Susan Viselli (E-Book available through KCU) (Unit V chapter 20-24): Regulation of Cell Growth and Cell Death) • Lecture slides and relevant citations listed on slides for specific subject

Recognize and discuss the basics of cancer cell biology (Ch. 22), including:

A. Know some historical perspective; classification (lecture slides)

B. Discuss and understand the multistep nature of cancer: i. Cancer initiation, promotion and progression ii. Proto-oncogenes; oncogene activation a. Viral Oncogenes – types and examples b. Mechanism of conversion of protooncogenes to oncogenes c. Defects in cell signaling pathways iii. Tumor suppressor genes a. Defects in cell cycle checkpoints b. Defects in cell death activation

C. Understand the components of the tumor microenvironment (lecture slides)

D. Clinical examples if cancer and defects in gene expression i. Breast Cancer ii. Head and neck cancer iii. Pancreatic cancer

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2
Q

What is a tumor?

A

Tumors - Space occupying lesions that may or may not be neoplasms

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3
Q

What is a neoplasm?

A

Neoplasm - relatively autonomous abnormal growth with abnormal gene regulation, 2 types: benign and malignant (→ cancer)

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4
Q

What is cancer?

A

Cancer - Malignant neoplasm (can produce metastasis)

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5
Q

What is metastasis?

A

• Metastasis - Secondary growth of cancer at different - location from primary neoplasm

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6
Q

Describe Multistep nature of cancer.

A
  • 1941 Isaac Berenblum: Showed mouse skin 2- step treatment model for cancer induction
  • Carcinogenesis involves at least 2 different distinct steps (multistep process)
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7
Q

What are the Stages of Carcinogenesis?

A

Initiation • Simple mutation in one or more genes that control key regulatory pathways of the cell

Promotion • Selective functional enhancement of signal transduction pathways that were induced by initiator by continuous exposure

Progression • Continuing change of the basically unstable karyotype

Stages of Carcinogenesis

  • Initiation - Genotoxic event - (Change in DNA sequence)
  • Promotion - Epigenetic event -(involving changes in gene regulation)
  • Progression - Clastogenic events and other (further changes in karyotype)
  • Cancer is largely the result of acquired genetic and epigenetic changes
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8
Q

Describe Initiation.

A
  • Irreversible
  • No threshold
  • Genotoxic agents include chemicals, radiation, reactive oxygen species, and viruses
  • Involves sequence change in cellular DNA
  • Single gene mutation, chromosomal translocation, and gene amplification
  • Can be a result of the activation of oncogenes or the inactivation of tumor suppressor genes
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9
Q

Describe Promotion.

A
  • Follows initiation
  • Promotion occurs over a long period of time • Reversible in its early stages
  • Involves gene activation or repression such that the latent phenotype of the initiated cell becomes expressed through cellular selection and clonal expansion.
  • Threshold exists (time and dose)
  • Various mechanisms such as
  • Inhibition of cell death of in the initiated cells
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10
Q

Describe Progression

A

Involves further complex genetic changes (chromosomal translocations, deletions, gene amplifications)

  • Irreversible changes in gene expression.
  • Evolution of karyotypic instability.
  • Selection for optimal growth in response to the cellular environment.
  • Results in the conversion of benign tumors into malignant neoplasms. capable of invading adjacent tissues and metastasizing to distant sites.
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11
Q

What are the Hallmarks of cancer?

A
  • Acquire self-sufficiency of growth signals
  • Become insensitive to growth inhibitory signals
  • Evade cell death
  • Acquire limitless replicative potential
  • Sustain angiogenesis
  • Acquire capabilities to invade tissues and metastasize
  • Create genome instability
  • Promote inflammation
  • Avoid immune destruction
  • Reprogram energy metabolism
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12
Q

What are Oncogenes & Tumor suppressor genes?

A
  • Oncogenes. These cellular genes whose expression stimulate cell division and/or growth. Expression of these genes is tightly control under normal circumstances. Loss of regulation of gene expression can lead to enhanced expression of these proteins which leads to unregulated cell division and growth.
  • Tumor suppressors. These are cellular genes that serve to check or inhibit cell division. Loss of expression of these proteins leads to cell growth or cell division.
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13
Q

Describe oncogenes in detail

A
  • In carcinogenesis: activated by mutations or overexpression.
  • Germline inheritance rarely involved.
  • Oncogenes are said to be “dominant” in their action. This is because they result from a “gain of function” mutation that results in their overexpression or unregulated activity (i.e., they remain constitutively active).
  • Since they promote cell growth and proliferation, their unregulated activity would provide a continuous stimulation of cell division. Because of this dominant action, it is only necessary that one of the two alleles be activated for the effects on cell growth to be felt.
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14
Q

What are the 3 forms that oncogenes are found in?

A

Oncogenes are found in three forms:

  • Cellular proto-oncogenes that have been captured by retroviruses,
  • Virus-specific genes that behave like cellular proto-oncogenes that have been mutated. (When the chicken made history –Discovery of Avian sarcoma virus, 1911 (Peyton Rous) - Viral oncogenes)
  • Cellular proto-oncogenes that have been mutated,

When a mutation or rearrangement event is involved, it is said that the protooncogene has been “activated.”

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15
Q

Describe Tumor suppressor genes in detail.

A
  • Recessive
  • Normal activity: repress growth
  • In carcinogenesis: inactivating mutations, deletions, loss of expression,
  • Germline inheritance frequently involved in cancer development
  • No known analogous in oncogenic viruses
  • Major examples are: p53, Rb, p14ARF, p16INK4A • All are cell cycle regulatory proteins
  • p53
  • p16INK4A – Numerous studies showed inactivation of the INK4a locus on human chromosome 9p21 in human cancers (2nd most commonly inactivated gene) • Gene mutation • Gene deletion • CpG island methylation in promoter
  • Rb (Retinoblastoma) – Not limited to loss of both alleles leads to RB.
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16
Q

Describe The Tumor Microenvironment (TME)

A
  • The tumor microenvironment is the tissue environment in which cancer cells exists, that include normal cells, secretory factors, and the extracellular matrix.
  • Cellular components (non-cancerous cells): – Immune cells : lymphocytes, macrophages, bone marrow-derived inflammatory cells – Fibroblasts, other stromal cells that are tissue specific such as stellate cells in the pancreas and glial cells in the brain – Blood vessels cells: endothelial cells and smooth muscles cells – Epithelial-mesenchymal transitions (EMTs) cells
  • Secretory factors: signaling molecules, growth factors, inflammatory factors, and enzymes (MMPs)
  • Extracellular matrix: Fibrous proteins and Proteoglycans. Provide structural support for multicellular environment
  • Barrier for therapy
  • Paracrine signaling
  • Desmoplastic reaction
  • Promoting tumor progression, therapy resistance and recurrence
  • EXAMPLE: Chronological aging of fibroblasts contributes to the pancreatic cancer progression and that the inflammatory mediators ALOX12 and 12-(S)-HETE may be potential stromal (TME) targets for interventions that seek to halt progression and improve therapy outcomes.
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17
Q

What is breast cancer?

A
  • Breast cancer is the most frequent malignancy in women worldwide
  • It is curable in ~70–80% of patients with early-stage, non-metastatic disease
  • Advanced breast cancer with distant organ metastases is considered incurable with currently available therapies.
  • On the molecular level, breast cancer is a heterogeneous disease; with molecular features include:
  1. Activation of human epidermal growth factor receptor 2 (HER2, encoded by ERBB2),
  2. Activation of hormone receptors (estrogen receptor and progesterone receptor)
  3. BRCA mutations
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18
Q

Describe Estrogen Receptor signaling pathway re: breast cancer

A
  • Estrogen Receptor signaling pathway
  • Breast cancer cells have relatively high ERα expression and low ERβ expression.
  • These two types of nuclear hormone receptors form homo- or heterodimers upon ligand binding and translocate into the cell nucleus for transcriptional regulation, which is the main function of ERs.
  • ER dimers bind to the ERE region of target genes and recruit co-regulators to achieve the regulation of transcriptional activity.
  • Another mechanism by which ERs control the expression of target genes is acting as a coregulator for other transcription
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19
Q

Describe the HER2 signaling pathway re: Breast cancer

A
  • HER2 signaling pathway.
  • HER2 as well as the other members of the EGFR family are receptor tyrosine kinases which are located on the cell membrane and responds to a wide variety of ligands.
  • Phosphorylation of the tyrosine kinase domain in the cytoplasm initiates downstream oncogenic signaling pathways such as PI3K/AKT pathway and Ras/MAPK pathway.
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20
Q

Describe Head and neck cancer

A
  • Approximately 500,000 newly diagnosed HNSCC each year worldwide (www.who.int)
  • In 2016, 62,000 new cases of HNSCC will be diagnosed in the US. (www.cancer.net)
  • Two-thirds of HNSCC are presented with locoregionally advanced disease.
  • Recent studies show an increase is HNSCC due to human papilloma virus infections HPV
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21
Q

What is pancreatic cancer?

A
  • The most common exocrine pancreatic neoplasm is pancreatic ductal adenocarcinoma PDAC, which accounts for more than 95% of all pancreatic malignancies
  • Pancreatic epithelial neoplasia is a multistep process
  • K- ras mutation is believed to be an early genetic event, followed by loss of functional p16 , p53, SMAD4, and many other changes
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22
Q

LO #3 Cell Cycle, Cancer, and Cell death

A

Identify and discuss the different types/mechanisms of cell death: (Ch. 23) A.Recognize the 5 major types of cell death i. Understand the importance of cell death. ii. Know cell death is mostly a cell cycle event. iii. Identify each type i. Necrosis (Ch. 23) ii. Apoptosis (Ch. 23) iii. Autophagy (Lecture slides) iv. Mitotic catastrophe (Lecture slides) v. Senescence (Ch. 24) • Differentiate between each type by identifying • morphological changes • cells involved • inflammatory outcome • major biochemical features • Describe the basic regulatory mechanisms B. Discuss basics of cancer therapy ((lecture slides) i. Different types of therapies a. Radiation therapy b. Chemotherapy c. Immunotherapy ii. Targets of therapy (cell death activation)

23
Q

Describe the Mechanisms of cell death

A

• Death is a good thing for two major reasons:

  1. In cancer cells to maximize cell killing.
  2. In normal cell to prevent genomic instability and malignant transformation due to damage .
  • On of the main trigger for cell death is DNA damage specifically DNA double-strand breaks which have long been thought to be the most important for cell killing.
  • Cell death occurs when they loss of large amounts of genetic material due to DNA damage as they divide reaching a critical level of genomic instability.
  • Cell death is mostly considered as cell cycle event due to the activation of cell cycle checkpoints.
  • Cell death can result from damages to other cellular targets:
  1. Cell membrane
  2. Cellular organelles such mitochondria and ER.
  3. Metabolic alterations
24
Q

What are the different types of mechanisms of cell death?

A

• Historically, three types of cell death have been distinguished in mammalian cells by morphological criteria:

– Type I : Apoptosis: Programed cell death (Suicide)

– Type II: Autophagy (Self destruction - digestion)

– Type III: Necrosis (explosive disaster)

• Now another two types are included also depending on their morphological criteria:

– Mitotic Catastrophe (well it is a catastrophe)

– Senescence (irreversible growth arrest – reproductive cell death)

Lack of cell cycle control make cancer cell difficult to kill

25
Q

What is necrosis?

A
  • Necrosis has been considered as an uncontrolled form of cell death.
  • Morphologically characterized by:
  1. Cell membrane: Swelling and rupture.
  2. Cytoplasm: Increased vacuolation, organelle degeneration, and mitochondrial swelling.
  3. Nucleus : Clumping and random degradation of nuclear chromatin and DNA (karyolysis)
  • Cells involved: All cell types.
  • Inflammation: Yes.
  • Biochemical features: Extensive failure of normal physiological pathways that are essential for maintaining cellular homeostasis, such as regulation of ion transport, energy production (ATP Depletion) and pH balance.
26
Q

What are the mechanisms of necrosis?

A
  • Initially suggested as uncontrolled form of cell death. Growing evidence supports the idea that necrosis can be regulated.
  • Two players are involved and target the mitochondria:
  1. Receptor-interacting protein 1 (RIP1)
  2. Poly [ADP-ribose] polymerase 1 (PARP-1)
  • Ca+2 overload
  • Mitochondrial uncoupling
  • Increased O2 consumption.
  • Excessive Reactive oxygen species (ROS) production
  • ATP depletion
  • No caspases involved
27
Q

What is apoptosis?

A
  • Also called programed cell death
  • Morphologically characterized by:
  1. Cell membrane: membrane blebbing and eventually fragmentation into membrane bound apoptotic bodies.
  2. Cytoplasm: Fragmentation and shrinkage
  3. Nucleus : Chromatin condensation and degradation via specific DNA cleavage leading to nuclear fragmentation.
  • Cells involved: hematopoietic cells and their malignant counterparts (liquid tumors). Apoptosis only plays a modest role in the treatment response of most solid tumors, which constitute the major part of human malignancies.
  • Inflammation: No.
  • Biochemical features: Cell membrane loses its asymmetry, and phosphatidylserine becomes exposed on the cell surface (eat me signal). Caspase (protease)/Mitochondria –dependent.
28
Q

What are the mechanisms of apoptosis?

A

• Triggers of apoptosis

  1. DNA damage ▪ ATM ▪ P53
  2. Death receptors signaling ▪ CD95, Fas receptor, TNF receptor superfamily ▪ Caspase-8 mediated
  3. Cell membranes ▪ Activation sphingomyelinase and leading to hydrolysis of sphingomyelin to ceramide.
  4. Mitochondrial damage ▪ Ceramide-mediated process ▪ mitochondrial ceramide synthase activation

Sensors: • ATM • Receptor • Mitochondria

Mediators: • p53 • anti-apoptotic BCL -2 family • pro -apoptotic BH3 family and BAX family • Cytochrome C • Apoptotic protease activating factor 1

Effectors: Caspases • Initiators : caspases 8, 9 and 10 • Executioner: caspases 3, 6 and 7

  • Bax and Bak are thought to induce permeabilization by forming pores upon oligomerization.
  • Pro -apoptotic BH3 -only family members (Bid, Bim, Bad, Noxa and Puma) activate Bax/Bak by one of these suggested ways:
  1. Binding of anti - apoptotic Bcl -2 proteins.
  2. BH3 proteins can directly bind and activate Bax and/or Bak
29
Q

What is autophagy?

A
  • Autophagy ‘self-eating’ and ‘Recycling’.
  • Process responsible for degrading longlived proteins and cytoplasm organelles, the products of which are recycled to generate macromolecules and ATP so as to maintain cellular homeostasis .
  • Mostly a survival mechanism in response to several stresses, such as DNA damaged, mitochondria, protein aggregation, pathogens, and nutrient starvation.
  • Morphologically characterized by:
  1. Cell membrane: membrane blebbing.
  2. Cytoplasm: accumulation of two-membrane autophagic vacuoles.
  3. Nucleus : Partial chromatin condensation No nuclear and DNA fragmentation.
  • Cells involved: All cell types
  • Inflammation: No.
  • Biochemical features: Caspase-independent and increased lysosomal activity.
30
Q

What are the mechanisms of autophagy?

A

• Autophagy is very complex process and involve many players:

  1. autophagy-related genes (proteins) (Atg)
  2. Coiled-coil myosin-like BCL2-interacting protein (Beclin-1)(Atg6) – initiation of the formation of the autophagosome (nucleation).
  3. Microtubule-associated protein 1A/1Blight chain 3 (LC3) – conjugation and elongation

Mechanisms:

  1. Release of Beclin from Bcl-2, which is then free to form the Class III PI3K that contributes to the formation of the nucleation complex.
  2. Two independent conjugation cascades, the LC3-II and the Atg5-12 cascades, serve to elongate the nucleation complex to generate the limiting membrane.
  3. The sole transmembrane atg, Atg9, delivers additional membranes for limiting membrane formation.
  4. The limiting membrane then sequesters cytosolic cargo and seals upon itself to form an autophagosome.
  5. The fusion of autophagosomes to lysosomes results in cargo degradation and release of nutrients into the cytosol.
31
Q

What is Mitotic catastrophe?

A
  • Mitotic catastrophe is defined as a type of cell death that is caused by aberrant mitosis.
  • In mammalian cells mitotic catastrophe is mainly associated with deficiencies in cell cycle checkpoints.
  • Morphologically characterized by:
  1. Cell membrane: No change
  2. Cytoplasm: larger cytoplasm with the formation of giant cell.
  3. Nucleus : micronucleation and multinucleation, nuclear fragmentation. Premature chromosome condensation. formation of nuclear envelopes around individual clusters of missegregated chromosomes
  • Cells involved: Most dividing cells
  • Inflammation: No.
  • Biochemical features: Caspase-independent (at early stage). abnormal CDK1/cyclin B activation
32
Q

What are the mechanisms for the induction of the mitotic catastrophe?

A

• mechanisms for the induction of the mitotic catastrophe.

  1. Defects cell cycle checkpoints I. p53 - G2 checkpoint. II. BUB-related kinase (BUBR) - spindle checkpoint. III. increased expression of multiple mitotic checkpoint genes (APC) – spindle assembly.
  2. Hyperamplification of centrosomes – Usually in subsequent cell cycle – CDK2/cyclin E/A (S-phase).
  3. Caspase-2 activation during metaphase – delayed apoptosis

• Fate of cells with aberrant mitosis

  1. Die without exiting mitosis - mitotic death.
  2. Proceed to G1 and continue division for many cycle (sometimes for years) then undergo cell death - delayed cell death.
  3. Exit mitosis and undergo permanent G1 arrest - senescence .
33
Q

What is senescence?

A
  • Permanent cell cycle arrest, reproductive death
  • Senescence derives from senex, a Latin word meaning old man or old age.
  • Senescence can be a replicative senescence related to telomere shortening.
  • Anti-transformation mechanism due to cellular damage.
  • Morphologically characterized by:
  1. Cell membrane: No change
  2. Cytoplasm: Flattening and increased granularity.
  3. Nucleus : Distinct heterochromatic structure
  • Cells involved: All types of cells
  • Inflammation: Yes but induced by secretory factors from the senescent cell it self.
34
Q

What are the mechanisms of Senescence?

A
  • Same as DNA damage responses that activate cell cycle checkpoints (i.e. ATM pathway).
  • Two pathways same fate:
  1. p53 – p21
  2. P16 -Rb
35
Q

Describe Basics of cancer therapy

A

The primary goal is to cure the patient, but it may also be to prolong life and enhance quality of life, or in worst case scenario relive symptoms such pain.

• Types of treatments

– Surgery (cut it out)

– Radiation therapy (zap it) – Cell damage - DNA

– Chemotherapy (poison it) – Cell damage - DNA

– Immunotherapy (attack it) – receptor based

  • The goal is to KILL CANCER (inducing cell death)
  • The Primary target of most approved therapies is DNA due to proliferative nature of cancer cells.
36
Q

Radiation is more effective on cells which have:

A
  1. Reproductive activity
  2. Cells which have longer dividing future ahead
  3. Cells with morphology and function are least fixed

How?:

  1. Direct deposition of energy to break DNA bonds
  2. Hydrolysis of water to produce powerful damaging free radicals
37
Q

Describe chemotherapy

A
  • Alkylating agents capable of denaturing certain macromolecules such as DNA macromolecules
  • Intercalating agents which interact with DNA and are intercalated between two bases, inducing a structural change and a functioning of this molecule– cleaving agents, capable of breaking DNA molecules.
  • Antimetabolites that can be structural analogues of purines or pyrimidines; they block the synthesis of the corresponding bases (5 FU), or folate analogues.
  • Mitostatic agents that inhibit tubulin synthesis, these being cell spindle poisons.
  • Platinum derivatives which plays a role by DNA binding
38
Q

Describe Adoptive T cell therapy (one type of immune therapy)

A

– Adoptive T cell therapy

  • Isolated T cells from the patient (or allogeneic donor) are genetically modified to express synthetic chimeric antigen receptors (CARs) that can bypass MHC restriction and direct specific cytotoxicity to a target molecule on the surface of the malignant cell.
  • CARs and then expanded and infused into the patient.
  • This overcomes the problem that tumor cells often downregulate MHC molecules, which leaves the cell unable to present antigen to conventional T cells
39
Q

Describe Personalized recombinant cancer vaccines (a type of immune therapy)

A

– Personalized recombinant cancer vaccines

  • Healthy tissue and tumor tissue from a patient with cancer are submitted for DNA sequencing and bioinformatic analyses to identify gene variants that encode peptides that are specific to the tumor (neoantigens).
  • Prediction algorithms are then used to screen for neoantigens that are likely to stably bind to the patient’s MHC (also known as HLA in human) molecules and their expression is validated by sequencing tumor mRNA.
  • Multiple predicted neoantigens are then formulated into vaccines, which are administered to the patient together with adjuvants.
  • Post treatment, the patient is regularly monitored for neoantigen-specific immune responses and tumor growth.
40
Q

Reference reading and LOs for cell cycle cancer death DSA

A

REFERENCE READING: References and citations for further reviewing and reading:

Lippincott’s Illustrated Reviews: Cell and Molecular Biology, 2e. 2019. Nalini Chandar and Susan Viselli (E-Book available through KCU) (Unit V chapter 20-24): Regulation of Cell Growth and Cell Death)

Lecture slides and relevant citations listed on slides for specific subject

Recognize and describe the following about the mammalian cell cycle (Ch. 20 and 21):

Cell cycle phases (G0/G1, S, G2, and M) (Ch. 20)

Understand importance of each cell cycle phase and what happens in each phase.

Learn the terms progression, transition and checkpoints.

Differentiate between each phase and basic research techniques utilized to identify the various phases of the cell cycle.

Regulation of cell cycle transition and progression (Ch. 21)

Identify the positive regulators of cell cycle progression (Cyclins and cyclin‑dependent kinases (CDK)).

Recognize the specific cyclin/CDK pair associated with each cell cycle phase and mechanism of action during phase transition.

Understand and describe regulatory mechanisms of cyclin/CDK pairs.

Checkpoints (block/delay) (Ch. 21)

Identify the negative regulators of the cell cycle (CDK inhibitors).

Recognize some of the mechanisms of cell cycle checkpoint activation and the role of different CDK inhibitors during different phases of the cell cycle.

Understand the outcomes of checkpoint activatio

41
Q

Describe Cell Division (M phase)

A

Cell Division (M phase)

Prophase – The cell begins to assemble the mitotic spindle, a set of microtubules extending from the centromeres which will later attach to the chromosomes.

Prometaphase – The nuclear envelope disintegrates, and the microtubules of the mitotic spindle attach to the chromosomes.

Metaphase – The chromosomes are aligned on the mitotic spindle. There is a pause here to allow all chromosomes to become attached.

Anaphase – The cohesion proteins which bind the sister chromatids together are cleaved and the chromosomes are pulled apart by the mitotic spindle.

Telophase – The nuclear membrane reconstitutes around each set of chromosomes

42
Q

The cell cycle is not always “On”?

A

The presence of sufficient stimulus (conditions) will encourage a cell recently formed by mitosis to remain in the active growth-and-division cycle; their absence will trigger the default decision to proceed from mitosis into the G0, quiescent state

43
Q

What are the phases of the cell cycle?

A

M-phase: mitosis

G0-phase: quiescent, intact proliferation capacity, non-cycling

G1-phase (Gap 1): duration between completion of cell division and initiation of DNA replication where cells start building cell mass

S-phase (Synthesis): DNA replication

G2-phase (Gap 2): duration between completion of DNA replication and initiation of cell division

44
Q

Describe Cell cycle phase detection

A

How we know at what phase cells are during the cell cycle:

A population of cells is labeled with a fluorescent dye that binds DNA. The cells are then passed through a flow cytometer, which measures the fluorescence intensity of individual cells. The data are plotted as cell number versus fluorescence intensity, which is proportional to DNA content. The distribution shows two peaks, corresponding to cells with DNA contents of 2n and 4n; these cells are in the G1 and G2/M phases of the cycle, respectively. Cells in S phase have DNA contents between 1n and 2n and are distributed between these two peak

45
Q

What are the The cell cycle regulators?

A

Cyclins: 12 different cyclins

  • G1 (cyclins: C, D 1-3, E 1-2, F, G)
  • S (cyclin A)
  • G2/M (cyclins B 1-2)
  • Cyclin H, constitutive expression

Cyclin dependent kinases (CDKs)

  • CDK4/CDK6 binds with cyclin D
  • CDK2 binds with cyclin E and cyclin A
  • CDK1 binds with cyclin B

Cyclin dependent kinase inhibitors (CKIs)

  • INK4 Family (p16,15,18,19)
  • Cip/Kip families (p21-Cip1, p27-Kip1, p57-Kip2)
46
Q

Describe The cell cycle positive regulators –Cyclins - CDKs

A

They come in pairs

They have special bond

  • The PSTAIRE α-helix is present in all CDKs and is essential for binding of cyclins.
  • The activation loop, sometimes termed a T-loop, must be phosphorylated on a threonine residue by a CDK-activating kinase (CAK) in order for the catalytic function of a CDK to become activated

They have complex activation process

  • Cyclin dependent kinases have sites that can be phosphorylated.
  • Phosphorylation on one of these sites activates the Cdk-cyclin complex, while phosphorylation on the other two inactivates it.
  • For the complex to be active, therefore, it must be phosphorylated on the first site, but dephosphorylated on the other two sites by the protein phosphatase cdc25 (a, b or c).
47
Q

Describe The cell cycle negative regulators – CKIs

A

They block the action of CDKs

Ensure tight control of the cell cycle (Balance)

Activated upon cell cycle checkpoint activation

Inactivation by inhibitor binding and phosphorylation interference.

When INK4 binds, twisting of the Cdk upper lobe blocks cyclin binding or interferes with ATP hydrolysis.

When p27 or p21 binds, a loop insinuates into the upper lobe of the Cdk and blocks ATP binding

48
Q

Describe Cell cycle entry & progression

A

Extra cellular signals regulate cell cycle proteins and consequently control growth.

Too many signals!

Ras superfamily members are often called “small G proteins” or “small GTPases. Ras proteins receive their signals from catalytic receptors that have been activated by their ligand. The overall effects of Ras signaling often involve induction of cell proliferation – How?

The restriction point

The point where cells commit to divide

It is a one-way street no turning back

49
Q

Describe G1/S transition

A

When E–CDK2 complexes drive pRb hyperphosphorylation, this liberates E2F transcription factors from pRb control, enabling the E2Fs to trigger increased transcription of the cyclin E and E2F1 genes; this leads to the synthesis of more cyclin E protein and the formation of more E–CDK2 complexes, which function, in turn, to drive additional pRb phosphorylation. At the same time, the newly synthesized E2F1 protein drives its own expression, further amplifying its activity.

50
Q

Describe G2/M transition

A

Activation of CDK1/cyclin B at the G 2 /M boundary

Activation of CDK1/cyclin B at the G 2 /M boundary maintained by Cdc25

CDK1/cyclin B translocate to the nucleus

CDK1/cyclin B initiate spindle assembly

Activated anaphase-promoting complex (APC) destroy cdk1 freeing cyclin B for degradation

51
Q

What are the checkpoints of the cell cycle?

A

Cell cycle checkpoints are cellular mechanisms, which control the order and timing of cell cycle phase transitions and ensure that critical events like DNA replication and chromosome segregation are completed with high fidelity.

Checkpoints are biochemical circuits that detect external or internal stimuli and send appropriate signals to the cell-cycle system.

Checkpoints mostly activated by genotoxic stress mainly DNA damage

52
Q

Describe the G1 checkpoint.

A

G1 checkpoint

After DNA damage, two parallel checkpoint pathways target the activity of Cyclin/Cdk complexes

The slower pathway involves the stabilization of p53 and transcriptional upregulation of p21 which binds and inhibits the Cyclin/Cdk complexes.

The faster pathway acts via the activation of Chk2 and the inactivation of Cdc25. Thus, inhibitory phosphates of the CyclinE/Cdk2 complex can no longer be removed.

53
Q

True or False: cell cycle needs to stop from time to time

A

TRUE-The cell cycle must stop from time to time

The cell cycle is highly regulated process

It is important to understand the normal progression of cell into and out of the proliferation

Many physiological conditions depend on this highly regulated process.

An error/change/loss of control lead to many pathologies

SFM EXAM 2a/b 2020 (14 decks)

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