Cell Cycle and signaling Flashcards
Intracellular hormones
- lipid/fat soluble -> can cross plasma membrane
- receptors are in cytoplasm or nucleus
- Not soluble in plasma -> circulate bound to a protein
examples of lipid soluble hormones
- progesterone
- estrogen
- testosterone
- cortisol
- aldosterone
- thyroid hormone
circulatory protein for estrogen/testosterone
sex binding globulin (SBG)
circulatory protein for thyroid hormone
thyroid binding globulin (TBG)
circulatory protein for cortisol, aldosterone, and progesterone
corticosteriod binding globulin (CBG)
extracellular hormones
- Not lipid soluble
- bind to surface receptors
- can either directly drive cellular changes, or use 2nd messenger system
extracellular hormone receptors that don’t use 2nd messenger
- tyrosine kinase
* JAK/STAT
important 2nd messengers
- cAMP
- cGMP
- IP3
receptor tyrosine kinase
EX: insulin binds -> RTK auto-phosphorylates -> gene transcription
*NO 2nd messenger
•many growth factors also use RTKs: IGF-1 (insulin-like), FGF (fibroblast), PDGF (platelet-derived), EGF(epidermal)
JAK/STAT
- JAK = janus kinase -> tyrosine kinase enzyme
- STAT = signal transducer and activator of transcription
- when the receptor is bound, JAK is activated to phosphorylate STAT which can then activate transcription
hormones that use JAK/STAT
- many cytokines (IFN-γ, IL-2, IL-6)
- erythropoietin
- G-CSF (granulocyte-colony stimulating factor)
- thrombopoietin
- prolactin
- growth hormone
JAK2 mutation
•JAK2 = gene for cytoplasmic tyrosine kinase
•mutation -> increased tyrosine phosphorylation -> hypersensitivity to cytokines -> more growth/longer survival
∴associated with myeloproliferative disorders
adenylyl cyclase
converts ATP to cAMP
receptors that use cAMP as second messenger
G-protein linked receptors
Hormones that use cAMP as 2nd messenger
- hypothalamus -> CRH, GHRH
- ant. pituitary -> FSH, LH, ACTH, TSH
- parathyroid hormone (PTH)
- glucagon
- ADH
- Histamine (H2-receptor -> GI)
- hCG
- MSH (melanocyte stim)
guanylate cyclase
converts GTP to cGMP
substances that use cGMP as 2nd messenger
•BNP/ANP
•Nitric oxide
(all are vasodilators)
phospholipase C
converts PIP2 to IP3
phosphatidyl inositol bisphosphate; inositol triphosphate
receptors that use IP3 as second messenger
G-protein linke receptors
Hormones that use IP3 as second messenger
- hypothalamus: GnRH, TRH
- post. pituitary: oxytocin and ADH (only V1 receptor -> vasoconstriction)
- Histamine (H1 receptor -> skin lungs)
- angiotensin II
- gastrin
Cell cycle events
G1 -> S -> G2 -> M -> G1 or G0 (quiescent)
Interphase
G1, S, and G2
G1 phase
- synthesis of proteins and organelles
* length varies
mitogens
- extracellular signaling molecules
- stimulate cell division
- function via cyclin dependent kinases (CDKs)
Growth factor
stimulates growth in size
S phase
- synthesis of DNA
* chromosomes -> 2 sister chromatids
G2 phase
•growth in preparation for mitosis
G0 phase
- may occur in absence of mitogen stimulation
- non-dividing state
- most cells in our body are in G0, some permanently
Neurons and skeletal muscle cells are
in terms of cell cycle
- terminally differentiated
* permanent G0 state
Liver cells are
in terms of cell cycle
often in G0, but can divide if stimulated
fibroblasts and lymphocytes are
(in terms of cell cycle
enter/exit G0 many times in lifespan
labile cells
- bone marrow, GI epithelial cells, hair follicles
- rapidly divide -> rarely/never enter G0
- most effect by chemotherapy
mitosis
- shortest/most rapid part of cell cycle
* Prophase -> prometaphase -> metaphase -> anaphase -> telophase
prophase
- chromosomes condense
* spindle fibers form (mitotic spindle)
prometaphase
chromosomes organize on mitotic spindle
metaphase
chromosomes line up on metaphase plate
anaphase
chromosomes separate
telophase
- spindle breaks down
* cell divides
G1-S checkpoint
- prior to S phase entry
- where the cell commits to divide into 2 daughter cells
- mitogens activate CDK -> S phase
G2-M checkpoint
prior to mitosis
M phase checkpoint
prior to anaphase/cytokinesis
cyclin dependent kinases (CDKs)
- central components of cell cycle control
* always present, but inactive until cyclins activate it
cyclins
regulatory proteins that activate CDKs
cyclin-CDK complexes
- phosphorylate regulatory proteins
* allow progression through cell cycle
how does mitogen activation of CDK occur
bind cell surface receptor -> activate intracellular pathways -> increase G1 cyclin levels -> increase CDK activity
E2F proteins
- activated by cyclin-CDK complexes at G1-S checkpoint
* bind to DNA promoter regions -> activate genes necessary for entry to S phase
inhibition of E2F
•normally inhibited by binding retinoblasoma (rb) proteins
•phosphorylation of rb by G1-S-CDK releases inhibition
∴rb regulates cell growth (“tumor suppressor”)
ATM pathway
- =ataxia telangiectasia mutated
- activated by double stranded DNA breaks
- leads to phosphorylation of proteins -> cell arrest at G1-S checkpoint
ATR pathway
- =ATR and RAD3 related
- activated by single stranded DNA breaks
- leads to phosphorylation of proteins ->cell arrest at G1-S checkpoint
P53 protein
- major target of phosphorylation in ATM/ATR systems
- becomes phosphorylated with DNA damage ->induces transcription of P21 protein
- tumor suppressor
P21 protein
- binds to CDKs and inhibits their activity -> blocks progression through cell cycle
- tumor suppressor
retinoblastoma
- rare childhood eye malignancy
- mutations in RB1 gene -> codes for rb protein
- abnormal rb -> unregulated cell growth (via E2F)
Li-Fraumeni syndrome
- multiple malignancies at early age
* caused by mutations in tumor suppressor gene TP53 -> cell cycle not arrested to allow for DNA repair
Ras/Raf system
- many growth factors bind RTKs that activate Ras/raf system
- Ras uses GTP->GDP and binds to Raf (MAPKKK) -> phosphorylates MEK (MAPKK) -> phosphorylates ERK (MAPK) -> phosphorylates transcription factors (ie cyclin D and E)
- MAPK = mitogen activated protein kinase
cyclin D
- mitogen sensing
* expressed throughout cell cycle
Rationale for using radiation therapy for some cancers
Cleavage of DNA double strands crucial for S phase and rapidly growing cells
