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

synthesis of proteins and organelles length varies

Cell Cycle and signaling Flashcards by Rachel Hassler

Intracellular hormones

lipid/fat soluble -> can cross plasma membrane
receptors are in cytoplasm or nucleus
Not soluble in plasma -> circulate bound to a protein

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examples of lipid soluble hormones

progesterone
estrogen
testosterone
cortisol
aldosterone
thyroid hormone

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circulatory protein for estrogen/testosterone

sex binding globulin (SBG)

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circulatory protein for thyroid hormone

thyroid binding globulin (TBG)

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circulatory protein for cortisol, aldosterone, and progesterone

corticosteriod binding globulin (CBG)

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extracellular hormones

Not lipid soluble
bind to surface receptors
can either directly drive cellular changes, or use 2nd messenger system

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extracellular hormone receptors that don’t use 2nd messenger

tyrosine kinase

* JAK/STAT

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important 2nd messengers

cAMP
cGMP
IP3

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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)

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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

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hormones that use JAK/STAT

many cytokines (IFN-γ, IL-2, IL-6)
erythropoietin
G-CSF (granulocyte-colony stimulating factor)
thrombopoietin
prolactin
growth hormone

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JAK2 mutation

•JAK2 = gene for cytoplasmic tyrosine kinase
•mutation -> increased tyrosine phosphorylation -> hypersensitivity to cytokines -> more growth/longer survival
∴associated with myeloproliferative disorders

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adenylyl cyclase

converts ATP to cAMP

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receptors that use cAMP as second messenger

G-protein linked receptors

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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)

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guanylate cyclase

converts GTP to cGMP

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substances that use cGMP as 2nd messenger

•BNP/ANP
•Nitric oxide
(all are vasodilators)

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phospholipase C

converts PIP2 to IP3

phosphatidyl inositol bisphosphate; inositol triphosphate

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receptors that use IP3 as second messenger

G-protein linke receptors

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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

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Cell cycle events

G1 -> S -> G2 -> M -> G1 or G0 (quiescent)

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Interphase

G1, S, and G2

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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