Health and Disease - Cell Division Flashcards
what occurs during prophase
condensation of replicated chromosomes
centrosomes migrate away from eachother
what occurs during prometaphase
nuclear membrane retraction
kinetichores form on centrosomes to attach to spindle fibers
what occurs during metaphase
chromosome positioning on the metaphase plate in the centre of the spindle
what occurs during anaphase
separation of sister chromatids of each duplicated chromosome towards the spindle poles
what occurs during telophase
mitotic spindle disassembly
nuclear envelope reformation
structure and features of the mitotic spindle
microtubules are polarised
MT assembly is initiated at the - end
+ end is where most growth occurs
search for chromosomes via dynamic growth cycles
what does each centrosome consist of
a cloud of amorphous material around the pair of centrioles
pericentriolar matrix
what happens in the pericentriolar matrix
Microtubules nucleate projecting their fast-growing
plus-ends outward while their minus-ends
associated with the centrosome
function of microtubule associated coiled-coil proteins
link motor proteins to the centrosome
localise components of the cell-cycle control system
function of γ-tubulin ring complexes
drives microtubule nucleation
function and features of kinesin-5
two plus-end motor domains, which move on antiparallel microtubules in the
spindle mid-zone => pole separation by sliding antiparallel microtubules
function/features of kinesin-14
one minus-end motor domain, and can cross-link antiparallel interpolar
microtubules at the spindle mid-zone => pull the poles together.
function and features of kinesin 10/4
plus-end directed motors that associate with chromosome arms
=> push the attached chromosome away from the pole
features and function of dyneins
minus-end directed motors on astral microtubules => pull the spindle poles toward
the cell cortex and away from each other
what is a kinetichore
e is a multi-protein structure (50
different proteins) at the centromeric region of the
chromatid
function of the + end of kinetichore microtubules
bind to the outer site of the kinetichore
what is kinetochore microtubule attachment reliant on
Ndc80
function of Ndc80
maintains integrity of microtubule-binding sites of the kinetochore
controls kinetochore microtubules
dynamics by promoting local polymerization and
depolymerization of their plus-ends
function of cohesins
ring like proteins that hold together chromosomes at their centrosomes
what occurs once spindle-assembly checkpoint processes have been satisfied
Cdc20 triggers sister chromatid separation
function of Cdc20
activates the APC/C (anaphase-promoting complex/cyclosome) ubiquitin
ligase which polyubiquitinates a protein called securin
function of securin
inhibitor of separase
what happens once securin is degraded by proteosomes
separase cleaves the Scc1 component of cohesins resulting in their disassembly and separation of sister chromatids to the spindle poles
what is non-disjunction
chromosomes segregate in anaphase prior to attachment of the
kinetochores of all sister chromatids to mitotic spindle fibers.
how is non-disjunction prevented
Mad2 (mitotic arrest
deficient 2) and Bub1 complex which is known as the
spindle-assembly checkpoint (SAC) operates just prior
to anaphase
Mad2 binds to kinetochores that have not bound to
microtubules of the mitotic spindle
* Kinetochore binding activates Mad2, and inhibits the
activity of Cdc20 which controls the APC/C ubiquitin
ligase
* This delays degradation of securin and anaphase.
what increases the production of reactive oxygen species and what does it cause
Energy
proteotoxic and other aneuploidy associated stresses
activates p53 via ATM
what is are the courses of action p53 may take depending on the level of aneuploidy
cell cycle arrest
apoptosis
what is the LGN complex
an evolutionary conserved cortical force generator which orients the mitotic spindle
how is temporal and spatial regulation of LGN complex achieved
LGN protein expression increases during mitosis
restricts LGN complex formation to mitosis
function of chromatin-associated guanine nucleotide
exchange factor (GEF)
stimulates Ran (Ras-related nuclear) GTPase
function of Ran GTPase
restricts LGN localization to two
cortical crescents facing the spindle poles during
metaphase (and anaphase)
features and function of Polo-like kinase 1 (Plk1)
localized at the spindle poles
phosphorylates and negatively controls the cortical localization of dynein
what does the specific localization of the LGN complex determine
the site of force concentration on
astral microtubules and the axis of spindle orientation
what does the LGN complex direct and what does it cause
the recruitment of the minus-end-directed microtubule motor dynein
* The directed movement of dynein along astral microtubules generates pulling forces on the
spindle poles leading to the orientation and/or positioning of the spindle
how will cells orient their mitotic spindles
along their longest axis
what is the feature of an unpolarised cell
all the polarity components such as ECM are evenly localised throughout the cell
what are the steps for the establishment of cell polarity
1 - breaking symmetry via extrinsic cues/stochastically
2 - establishing spatial organisation via signallling transduction
3 - amplifying and maintaining polarity via feedback loops
what are the features of the crumb complex
an evolutionary conserved module
localised at the apical domain
Scaffold proteins associated with Pals1 and PATJ
what are the features of the Par complex
evolutionary conserved proteins to establish polarity including:
- Par3/6
- Cdc42
- aPKC
what are the features of the basolateral Scribble complex
evolutionary conserved module containing:
- Lgl
- Scribble
- Dlg
what does Par3 localise to
adherins junctions
what does Par1 phosphorylate, causing what
phosphorylates Par3
phosphorylated Par3 associates with Par5
leads to their cytoplasmic sequestration
what does Par3 help recruit
helps recruit E-cadherins to establish adherin junctions
what does activated Par3/Cdc42 recruit
they recruit Par6 and aPKC to the cortex
Par3 also recruits Par1
what occurs at stage 3 of polarity establishment
aPKC phosphorylates Par3
restricts Par3 to more basal location above adherin junctions
contributes to apical-lateral border
what occurs at stage 4 of polarity establishment
aPKC phosphorylation of Par3 disrupts the Par3-Pal1 interactions
Pal1 begins to stabilise Crumbs in the apical domain
how is cell polarity maintained
Par6-aPKC and scribble complexes maintain polarity through reciprocal inhibition
what is the effect of Par3 silencing
dramatically reduced tumour latency in mouse models of breast cancer
enhanced tumour growth
what is Par3 depletion associated with
induction of MMP9
destruction of ECM
invasion
how is Par3 expression affected in breast cancer
expression is significantly reduced
correlates with active aPKC and Stat3
what is MDM2
it is the E3 ubiquitin ligase of p53 that controls p53 levels via proteosomal degradation
structural features of MDM2
self destructive RING-finger-containing ubiquitination enzyme
what is Nutlin3a
small molecule that binds to MDM2’s p53 binding domain to disrupt the MDM2-p53 complex
what is HIL98
a small molecule that binds to MDM2 to inhibit the E3 ligase activity at the carboxyl terminus
what is RITA
a small molecule that blocks the MDM2-p53 complex by binding to p53
how is guidance of microtubule growth ordained
actin-microtubule crosslinking proteins associate with microtubules via +TIPS
provides dynamic link between actin and microtubules
regulates microtubule growth
how is anchoring and stabilization of microtubules achieved
protein complex associated with the cortical actin networks captures both the + and - minus ends of microtubules
what does actin form at the basal end
forms a membrane bound cortex along the cell wall
also forms a contractile belt on the apical face of the cortex
what is the apical-basal polarity maintained by
regulated interactions with the +/- ends of microtubules and the actin cortex at the basal and apical surfaces respectively
what are the minus ends of microtubules anchored by
actin crosslinking family protein 7 (ACSF7)
and
microtubule minus-end tracker calmodulin- regulated spectrin associated protein 3
(CAMSAP3)
what are the plus ends of microtubules anchored by
anchored by membrane bound LL5alpha/LL5beta in the presence of active integrins
this is done through end binding proteins (EB’s) and the cytoplasmic linker associated proteins (CLASP2)
what are microtubule minus ends captured by
captured by CAMSAP3 which interacts with p120-catenin
this is done through PLEKHA7
what are microtubule plus ends captured by
captured by +TIPs that interact with adherins junction’s via beta-catenin and p120-catenin
how do microtubules promote junction formation
delivering junction components
promoting recruitment and activation of myosin II - drives clustering of E-cadherins
function of kinesin KIF17 localised at microtubules plus ends
activates RHOA
promotes accumulation of junctional actin and adhesion stability
