Cell cycle stages (5)

G₀: resting phase (majority of cells at a given time are in this stage)

INTERPHASE: G1 (cell contents duplicated except for chrom), S (chrom duplication), G2 (double check)

Mitosis and cytokinesis

Retinoblastoma protein (pRb)

tumor suppressor protein important in preventing excessive cell growth

hypophosphorylated: inhibits cell cycle progression

phosphorylated (by CDKs and cyclins): inactivated-->cell cycle progresses

becomes more and more phosphorylated as cell cycle goes on, then becomes hypophosphorylated after mitosis

Rb1 gene

encodes for pRb in humans

mutation: protein inactivated-->retinoblastoma, eye cancer

mutation does not cause global effects, reason unknown

induced proteolysis

especially with proteins involved in phosphorylation/dephosphorylation, proteolysis is used to prevent reversal of reactions

regulates cyclins

cyclins

regulatory subunit, sequential activation ensures correct timing and ordering of cell cycle events

cyclin-dependent kinases (CDKs)

catalytic subunit, activated when bound to cyclin

cyclin-CDK pair allows phosphorylation to regulate and progress cell cycle

constitutively expressed (cyclin production is regulated)

CDK hyperactivity

underlying problem in hyperproliferation

cyclin C overexpression

found in CNS cells of Alzheimer's patients

cyclin E abnormalities

lung premalignancy or malignancy

negative marker for prognosis

cyclin A overexpression

found in tumors/cancer cell lines

accelerates pRb phosphorylation, promotes entry into S phase, associated with ability to grow in suspension

cell cycle checkpoints

G1 (**critical): cell size/ favorable envt

G2: cell size/ envt/ DNA replication

Metaphase: chromosome alignment on spindle

p53

tumor suppressor protein with role in G1 and G2 checkpoints

activates DNA repair when DNA is damaged

induces cell growth arrest if DNA is damaged (holds cell at G1/S)

initiates apoptosis if DNA cannot be repaired

targets cyclin E and cyclin A/CDK genes

p53 mutation

high likelihood of developing tumors early in life

p53 + Ras mutation

high likelihood of cancer (individually, the mutations have lesser effects on promoting cancer)

synergistically regulated "cooperation response genes," important mediators of tumor formation

cooperation response genes

important mediators of tumor formation

regulated by Ras and p53

when cell cycle failures occur

during or immediately after S phase--> apoptosis

during or after mitosis--> apoptosis

during G1/G2--> G1/G2 arrest

Apoptosis

programmed cell death

cell shrinkage, chrom condensation, nulclear collapse, apoptotic body formation and lysis

*no spillage of cell contents or inflammation of surrounding area

cell necrosis

traumatic cell death due to acute injury wiht spillage of cell contents into surrounding area

intracellular apoptotic inducers

lack of nutrients, low oxygen, heat, hypercalcemia

extracellular apoptotic inducers

hormones, toxins, cytokines, growth factor withdrawal

regulation of apoptosis

pro-apoptotic cytokines

TNF (tumor necrosis factor) + Fas ligand (transmemb protein)-->activate caspases (pro-apoptotic enz)-->activate DNases and degrade intracellular proteins

TNF and Fas ligand

tumor necrosis factor and fas ligand, a transmemb protein, activate apoptosis

progenitor cells

multipotent: give rise to multiple, but limited, cell lines

ex: hematopoietic cells-->all blood cell types

unipotent: give rise to only one cell/tissue type

ex: liver cells or skin cells

stem cells

self-renewal (indefinite mitosis)

totipotent (differentiate into any cell type and give rise to an entire organism, ex: zygote)

pluripotent (differentiate into any cell type but can't give rise to an entire organism bc can't differentiate into extrafetal tissue like placenta)

Embryonic stem cells (ESC)

-derived from ____

-can cause ___

derived from inner cell mass of blastocyst prior to implantation (from in vitro fertilized human embryos)

can cause teratomas upon implantation into a host

adult stem cells (ASC)

ex: hematopoietic cells in bone marrow or umbilical cord

can also be purified from peripheral blood after having been mobilized by G-CSF (colony-stimulating factor)

induced pluripotent stem cells (iPSC)

somatic cells which are reprogrammed to be pluripotent

adult cell nucleus injected into enucleated oocyte and treated w various factors

microchimerism

bidirectional trafficking and persistence of small numbers of cells within a person which originate from a different individual

Fetal microchimerism

cells from fetus (stem/progenitor cellos, lymphocytes and macrophages) travel thru placenta to mother

may establish cell lineages, multiply and remain for yrs

maternal microchimerism

less frequently, maternal to fetal transport

clinical significance of fetal-maternal microchimerism

-reduced GVH reaction than otherwise expected (induced tolerance)

-link between microchimerism and skin/muscle disease

-reduced breast cancer risk in women with fetal chimeric cells

-more fetal cells in maternal circulation when fetus is aneuploid (ex: trisomy 21 or 18)