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Cell 402 > A3-A4 > Flashcards

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
Q

_____ is a cell cycle integration point for cell signalling pathways

A

-MYC (directly represses expression of CKI and activates expression of cyclin D and E)

26
Q

how signals likes TGF-B,Wnt, SHH induce EMT/EMyoT

A

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
Q

gap junctions defined by which protein?

A

connexin

28
Q

adherens junctions defined by which protein?

A

e-cadherin

29
Q

tight junctions defined by which protein?

A

-jam (junction adhesion molecule)
-occudlin
-claudin

30
Q

tight junctions do what? adherens? desmosomes? focal adhesion? hemidesmosome?

A

-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
Q

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

A

-Cell Adhesion Molecules (CAMs)

32
Q

Epithelial (E)-cadherin (def.)
Integrins (def.)

A

-one type of cell-cell CAM
-bind the extracellular matrix (ECM)

33
Q

Cadherins (def.)

A
  • 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
Q

complex joining activated e-cadherin

A
  • 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
Q

How Rho,Rac Cdc42 work?

A

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
Q

protein complex formation in tight junction

A

JAM, Z01

37
Q

protein complex formation in focal adherenes

A

FAK
* α-Integrin
* β-Integrin

38
Q

how focal adhesions work?

A
  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
Q

β1 integrin and
the cell cycle

A

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
Q

ROCK – Rho-associated
protein kinase

A

Rho-GTP activates ROCK

41
Q

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
.

A
42
Q

Epithelial cell divisions
are coordinated with
cell loss to preserve
epithelial integrity

A
  • 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
Q

Niche – a combination of factors
external to the cell that influence how
it behaves.

A
44
Q

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).

A
45
Q

Eg5 (Kinesin-5) generates anisotropic cell
elongation pushing daughter cells apart
during telophase/cytokines

A
46
Q

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.

A
47
Q

Talin - forms the mechanical link between the cytoplasmic domain of integrins and the actin cytoskeleton
* Rho and Rho Kinase (ROCK)
* YES associated Protein (YAP)

A
48
Q

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

A
49
Q

Atomic force microscopy (AFM)

A
50
Q
  • Transient receptor potential cation
    channel subfamily V member 4
    (TRPV4 ) Mechanosensitive ion channel
  • ERK1/2 – part of the MAPK
    transduction pathway
A

increase pressure increase in proliferation

51
Q

Piezo1

A

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
Q

The HIPPO pathway

A
  • 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
Q
A

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
Q

The YAP/TAZ + TEAD transcription
factor complex regulates substratedependent cell proliferation

A
  • 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
Q

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

A
56
Q

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.

A
57
Q

Snail/Slug proteins coordinate EMT inhibit e.cadherin (epithelial markers) activartes Rho GTPases and fibronectio. and vitamentin

A
58
Q

Essentially, MET is just the EMT in reverse – as
homophilic Cadherin interaction (primordial junctions)
lead to reassembly of the tight and adherens junctions.

A
59
Q
  • 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
A

Cell 402 (5 decks)

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