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A3-A4 Flashcards

1
Q

terminal differentiation (def.)

A

When an animal cell reaches its final functional form it is highly unlikely to divide or differentiate further

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2
Q

Senescence (def.)

A

cells lose their ability to progress through a lineage (cannot divide or differentiate properly)

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3
Q

‘Circuits’ regulating ___, ______,______ and ____ all affect the cell cycle

A

-motility (coordinated with cell cycle)
-proliferation (induce cell cycle)
-differentiation (exit cell cycle)
-survival (cytostasis - G0/quiescence)

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4
Q

cell signalling: relay proteins? messenger? adaptor? amplifier? transducer? bifurcation? integrator? latent gene regulatory protein?

A
  • pass on message
    -one part of the cell to another
    -link one protein to another
    -increase signal
    -change form of signal
    -one pathway to another
    -join two pathways
    activated at cell surface and then move to nucleus
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5
Q

most of the signals that affect cell cycle are from ____

A

outside the cell (extrinsic)

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6
Q

how WNT pathway works?

A

-WNT (extracellular signal) binds to membrane receptors (LRP and Frizzled)
-activated receptors activate dishevelled protein which inactivated GK3B kinase
-kinase can’t phosph. B-catenin to tagret for ubiquitin and degradation by proteosome
-B-catenin moves to nucleus and displaces groucho protein which suppreses TCF/LEF1 TFs

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7
Q

what sequesters B-catenin when Wnt signal is not present?

A

axin (scaffold) holds GSK3B and B-catenine and APC (adenomatous poluposis coli), allowing kinase to po4 B-catenin for destruction

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8
Q

how is cyclin d and cyclin e regulated by wnt signalling?

A

GSK3 inhibits cyclin D, E and activates p21 and p27 that inactivate cyclin e/d to control entry into G1/S transition , B cat also affects c-myc transcription which alos inhibts p21/p27

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9
Q

how HH pathway works?

A

Binding of Hh to the Patched (Ptch) & Hedgehog interacting protein (Hip) coreceptor inhibits Ptch mediated repression of Smoothened (Smo).
This activates the modulator protein Fused to inhibit the anchoring of
Glioma Associated (Gli) transcripton factor in the cytoplasm by Suppressor of Fused (Sufu). Gli translocases to the nucleus (both activating and repressive forms)

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10
Q

____ regulates the cell cycle in developing human brain cells. HH (SHH) regulates progression into _______ by inducing Cyclin D and Cyclin E gene expression. Activation of the SHH pathway also somehow inhibits _____ (mechanism unknown). _____also inhibits Cyclin in
neuronal cell linages.

A

-SHH
-late G1 phase
-p21
-Patched1 (Ptc1)

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11
Q

Notch is a special type of extrinsic signal in that the ligand _____ and receptor (Notch) remain attached to the cell. Thus, two cells must be in very close contact for the Notch signalling pathway to be activated.The cellular transmission of activated Notch occurs via proteolytic cleavage of the _______ which goes to the nucleus and acts as a transcription factor.

A

-(Delta or Jagged)
-Notch Intracellular Domain (NICD)

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12
Q

Notch mediated lateral inhibition during neuronal cell differentiation

A

Initially, epithelial cells divide but remain in an equally primitive state, each expressing relatively the same amount of Notch and Delta.
Cell specialization genes are inhibited as is any change in Delta expression.
* In a few cells slightly higher activation of Notch leads to reduced expression of Delta.
* This competition eventually leads to only one cell in a group with active Delta which suppresses specialization of its neighbours.
This cell also becomes insensitive to Notch signalling leading to loss of repression of genes that promote a neuronal linage (specialization).

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13
Q

The Delta/Notch signalling circuit drives _____differentiation.Transcription factors and other related proteins
that induce a neuronal lineage (neuroprogenitor) are called “Proneural’.
Proneural genes cause cells to follow a neuronal lineage, but also induce expression of _____.

A

-epithelial -> neuronal
-CKIs

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14
Q

Asymmetric cell division drives bristle lineage via _____

A

asymmetric activation of E3 ligases by NUMB

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15
Q

Notch and HH effect on Cyclin E

A

can work with E3 ligases to ubiquitinate and degrade cyclin E

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16
Q

steroid hormones enter the cell and have which domains in their receptors (progesterone receptor, androgen receptor, estrogen receptor)

A

NTD (n-terminal domain)
DBD (DNA binding domain)
LBD (ligand binding domain)

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17
Q

estrogen/androgen and the cell cycle

A

estrogen + receptor can up regulate transcription of Myc; sequester p21/p27 away from (cyclin E/A)/CDK2; estrogen +ER regulates RPRM gene that encodes G2 regulatory protein; Androgen +AR and Estrogen +ER compete at the promoter of the CCND1 gene that encodes Cyclin D1

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18
Q

how does RTKs work?

A

RTKs act as dimers that cross phosphorylate the other subunit. When activated, RTKs can phosphorylate cytoplasmic proteins like GRB2 (Growth Factor Bound Protein 2) which activates GEF proteins. Activated (GTP bound) RAS signal is
transduced through the MAPK cascade activating/repressing genes affecting cell function

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19
Q

RAS –PiP3/AKT pathway

A

Activation of phosphatidylinositol 3-kinases (PI3Ks) occurs after stimulation of receptor tyrosine kinases (RTKs) and
assembly of receptor–PI3K complexes.
* These complexes localize at the membrane conversion of PtdIns(4,5)P2 (PIP2) to PtdIns(3,4,5)P3 (PIP3).
* PIP3 is a relay protein that activates AKT (protein kinase B)
* PTEN blocks phosphatidylinositol 3 kinase
(PI3K) signaling by inhibiting PIP3 dependent processes such as the membrane recruitment and activation of AKT.

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20
Q

Locally high surface levels of an individual RTK may promote ______ and/or clustering.

A

-homodimerization

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21
Q

There are multiple known ‘growth factor’ / mitogen proteins in mammals ; have their own RTK

A
  • Epidermal Growth Factor (EGF)
  • Fibroblst Growth Factor (FGF)
  • Nerve Growth Factor (NGF)
  • Insulin and Insulin-like Growth Factor (IGF)
  • Platlet Derived Growth Factor (PDGF)
  • Transforming Growth Factpr β (TGFβ)
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22
Q

Activated RAS induces expression of _____

A

Cyclin D1 and p21 CKI (CyclinD1/CDK4 and CyclinD1/CDK6
complexes are partially active even with p21
CKI present and this leads to some
phosphorylation of RB.)
-Myc expression and entry into S phase

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23
Q

anti mitogens like TGF-β and BMPs promote activity of _______

A

-CKI-p21(Cip1) to promote cell differentiation

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24
Q

TGF-β and Bone Morphogenetic Proteins (BMPs) pathway

A

TGF-β binds to TGF-β-Receptor (Type I and Type II) and activates TGF-β SMADs 2/3 (associate with Smad4 and translocate to nucleus as TF)
-BMP: smad2/3 is replaced with smad 1/5/8
-TGFB inhibits CAK
-TF smad complex increase transcription of p21/p15

25
_____ is a cell cycle integration point for cell signalling pathways
-MYC (directly represses expression of CKI and activates expression of cyclin D and E)
26
how signals likes TGF-B,Wnt, SHH induce EMT/EMyoT
Signals like TGF-β can induce epithelial cells to lose Epithelial (E)-cadherin-mediated adhesion to each other. * These cells become more less epithelial and more fibroblast-like and can even move/migrate through the body * Myofibroblasts are fibroblasts that express muscle proteins like α–Smooth Muscle Actin (αSMA)
27
gap junctions defined by which protein?
connexin
28
adherens junctions defined by which protein?
e-cadherin
29
tight junctions defined by which protein?
-jam (junction adhesion molecule) -occudlin -claudin
30
tight junctions do what? adherens? desmosomes? focal adhesion? hemidesmosome?
-seals cells in a layer (connects to actin cytoskeleton) -joins actin bundles (force transfer) -joins IF (keratins,desmins, vimetin) -anchor MF to ECM -anchors IF to ECM
31
Cells can ‘sense’ the relative number of cells in their vicinity through ______ which affects the cell cycle. * Loss of, or mutation of CAMs causes a loss of contact inhibition of proliferation
-Cell Adhesion Molecules (CAMs)
32
Epithelial (E)-cadherin (def.) Integrins (def.)
-one type of cell-cell CAM -bind the extracellular matrix (ECM)
33
Cadherins (def.)
* Calcium-dependent adhesion * Transmembrane protein with extracellular Ectodomain (EC) repeats. * Requires Ca2+ ions for function * Cytoplasmic domain binds β-catenin and other proteins adjacent to the plasma membrane linking to the actin (microfilament) cytoskeleton * Activated as a dimer * Binds a protein complex to link it to the actin cytoskeleton -part of adherens junction
34
complex joining activated e-cadherin
* p120 catenin (p120) – suppresses Cadherin endocytosis * α-catenin – links Cadherins to microfilaments (actin cytoskeleton) * Vinculin – links α-catenin and Integrin to microfilaments * α -actinin – cross-links F-actin microfilaments * Formin proteins (Fmn) – promote assembly of globular actin (G-actin) into F-actin * Filamentous (F) Actin
35
How Rho,Rac Cdc42 work?
Rho, Rac and Cdc42 are GTP activated proteins. * In the presence of Ca2+, when cells with homotypic Cadherins come into contact, the Cadherin ECM regions bind and the molecules cluster. * The cytoplasmic domain of Cadherin binds β –catenin and α –catenin. * Activation of Rho, Rac and/or Cdc42 regulate effector molecules that bridge the catenin complex to the cytoskeleton, polarizing an epithelial cell.
36
protein complex formation in tight junction
JAM, Z01
37
protein complex formation in focal adherenes
FAK * α-Integrin * β-Integrin
38
how focal adhesions work?
1. Forces within the cell (cytoskeleton) via actin/myosin affect mechanosensitive proteins in the actin-linking module to form a mechanoresponsive network. 2. The effect on the actin cytoskeleton helps integrate the response with the matrix. 3. Stimulation of the signalling module eventually leads to activation of GEFs and GAPs, leading to activation of Rho and Rac. 4. These G affect cytoskeleton-regulation. 5. This in term feeds back to the force-generating cytoskeletal elements.
39
β1 integrin and the cell cycle
Linked to epidermal growth factor receptor – signals through Ras pathway to modify the cell cycle 1) activates Raf – Rapidly Accelerated Fibrosarcoma –Ras effector (Mitogen -activated - protein [MAP] kinase) * MEK – MAP/ERK kinase kinase * Erk – Extracellular signal Regulated kinase and Ras then Erk can activate CycD/CDK4/6 to po44 rb intergin can also prevent p21/p27 inhbition of cycE/CDK2
40
ROCK – Rho-associated protein kinase
Rho-GTP activates ROCK
41
When localized to the cytoplasm, Cip/Kip family proteins (p27 (KIP1), p21 (CIP1) and p57 (KIP2) inhibit the Rho -signalling pathway, affecting cytoskeletal organization and cell motility. * Cip/Kip proteins inhibit the Rho pathway at distinct points, the phenotypic consequences of this inhibition is a net decrease in Rho -induced formation of actin stress fibres and focal adhesions .
42
Epithelial cell divisions are coordinated with cell loss to preserve epithelial integrity
* Loss of cells in an area ‘wound’ is sensed as a change in local cell density via the strength cell -cell adhesion via E - cadherin. * This change in tension directly reduces the activity of the Wee1 kinase that phosphorylates & inhibits CDK1/CycB (Lecture 1.21). * This leads to a local increase in cell proliferation to produce epithelial cells to ‘heal’ the wound.
43
Niche – a combination of factors external to the cell that influence how it behaves.
44
Mutations in E-cadherin and other adhesion molecules, the WNT signalling protein adenomatous polyposis coli (APC) and p53 may impair the proper organization of the spindle and misoriented cell division, leading to alterations in differentiation dysregulation of the cell cycle (cancer).
45
Eg5 (Kinesin-5) generates anisotropic cell elongation pushing daughter cells apart during telophase/cytokines
46
The process of “mitotic rounding” generates force on the surrounding cells and the basal membrane depending on the original cell morphology. * During cell division kinesin proteins push the poles apart in the plane of the mitotic spindles. * Post -division, cells return to their characteristic shape and attachments which also generates force.
47
Talin - forms the mechanical link between the cytoplasmic domain of integrins and the actin cytoskeleton * Rho and Rho Kinase (ROCK) * YES associated Protein (YAP)
48
Cells embedded in the extracellular matrix (ECM) sense stiffness and viscoelastic properties of the matrix through integrin binding, activation and clustering, while sensing confinement, viscoelasticity and plasticity through cell volume changes and ion channel activation, which leads to Ca2+ ion influx
49
Atomic force microscopy (AFM)
50
* Transient receptor potential cation channel subfamily V member 4 (TRPV4 ) Mechanosensitive ion channel * ERK1/2 – part of the MAPK transduction pathway
increase pressure increase in proliferation
51
Piezo1
Lecture A4.30 * Mechanosensitive Ca2+ channel * Signals via Akt kinase pathway Akt – “a serine/threonine protein kinase encoded by the oncogene in the transforming retrovirus isolated from the thymoma cell line AKT-8, which is derived from the Stock A Strain k AKR mouse ” mTOR - Mammalian target of rapamycin. mTor regulates cell proliferation, autophagy, and apoptosis by via multiple signaling pathways
52
The HIPPO pathway
* SALVADOR1 (SAV1) * Macrophage Stimulating (MST) 1 & 2 (Kinases) * Large tumor suppressor kinase (LATS) 1 & 2 * MOB1A & B(Kinase Activator) * 14-3-3 * A family of scaffold proteins * TEAD * DNA binding transcription factor that requires co-factors to activate genes * YAP (YES associated protein) * TAZ (Transcriptional coactivator with PDZ-binding motif) * VGLL4 – Vestigial-Like 4 – a transcriptional repressor
53
Hippo pathway proteins (red) interact with WNT (dark blue), TGFβ/ BMP (light blue), HH (pink) and other receptors (green). * WNT and Hippo pathways intersect at two points: * phosphorylated transcriptional co-activator with PDZbinding motif (TAZ) can activate Dishevelled (DVL) and thereby repress β-catenin. * Yes-associated protein (YAP) can form a physical complex with β-catenin and cooperatively regulate transcription. * Phosphorylated (P) YAP and TAZ can bind SMAD2 and SMAD3 and repress them by promoting cytoplasmic localization, influencing TGFβ. * YAP can physically complex with SMAD1 and drive transcription together with SMADs downstream of BMP. * HIPPO signalling vial LATS1 and LATS2 can be modified by SMAD1-4. * YAP induces expression of GLI2 (Ci) – part of the HH pathway. * Dashed arrows represent the translocation of the YAP or TAZ transcriptional regulatory proteins to the nucleus.
54
The YAP/TAZ + TEAD transcription factor complex regulates substratedependent cell proliferation
* HIPPO response to cell adhesion, substrate stiffness, cell density, shear forces or other pressures is regulated by regulated trafficking of the YAP/TAZ cofactor proteins in or out of the nucleus.
55
Cells can transition between a motile (mesenchymal) and epithelial (static, highly adhered to their neighbours) * EMT/MET and related processes are a normal process needed for early development as well as step in cancer progression * Contact between cells and between cells and substrates strongly affects the cell cycle * Contact inhibition * MET is just EMT in reverse
56
Growth factor (mitogenic) signalling is integrated with WNT and TGF-β signalling at the level of the SNAIL/TWIST transcription factors to induce the EMD.
57
Snail/Slug proteins coordinate EMT inhibit e.cadherin (epithelial markers) activartes Rho GTPases and fibronectio. and vitamentin
58
Essentially, MET is just the EMT in reverse – as homophilic Cadherin interaction (primordial junctions) lead to reassembly of the tight and adherens junctions.
59
* Cancer cells have often lost many cell-intrinsic cell-cycle regulatory mechanisms but often retain mechanosensitive cell cycle regulation pathways * As a tumour grows, this causes cell-crowding and increased hydrostatic pressure – inhibits the cell cycle. * The ECM surrounding tumours is ‘stiffer’ – promotes the cell cycle * Other microenvironmental changes associated with tumour formation may affect mechanical forces that can promote cell proliferation

Cell 402 (5 decks)

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