principles of pharm final Flashcards
explain mechanism of rtk
1) hormone binds to extracellular domain = tyrosine kinase receptors dimerize
2) dimerize -> phosphorylates the C terminal tyrosine residues (active rtk)
3) intracellular signaling proteins are bound to it -> signal relayed by activated signaling proteins into the cell’s interior
4) adaptor protein attaches and has ras-activating protein attached
5) ras activating protein makes inactive ras protein + gdp -> active ras protein with gtp
6) the active ras protein continues transmitting signal
7) activates raf, mek, and erk = leads to changes in protein activity and gene expression
what is an adaptor protein?
a protein which is accessory to main proteins in a signal transduction pathway
lacks intrinsic enzymatic activity, mediates specific protein-protein interaction
? was is ras?
rat sarcoma protein
many tumor cells contain a mutant ras
function: activates protein kinase raf and PI3K (phosphatidylinositol 3 kinase
? what is raf?
raf - rapidly accelerated fibrosarcoma
1st of the kinases that leads to activation of ERK and then transcription of specific genes
know regulation of a Ras (a GTPase) activity
1) inactive ras -> GEF (guanine nucleotide exchange factor)
2) active ras -> downstream signaling
3) GAP (gtpase activating protein) induced gtp hydrolysis and ras inactivation
cytokine superfamily receptors
- no catalytic domain
- interact withs non receptor protein tyrosine kinases to phosphorylate the receptor (no auto phos) ex: JAK (janus kinase)
jak/stat pathway
- more immediate connection to transcription by directly affecting transcription factors
(jak phosphorylates receptor and stat (only when stat is binded to receptor)
know oncogene mechanism
reduce dependence on growth signals by: producing their own GF, overexpression of GF receptors, alterations to intracellular components of signaling pathways
how ras mutations lead to cancer
-single point mutation in ras inhibits gtpase activity and prolongs active state
- mutations enhances rate of dissociation of bound gdp
= unregulated MAP cascade = inc cell proliferation
rtks as drug targets (unsure)
1) growth factors (using antibodies)
2) soluble receptors
3) tyrosine kinase inhibitors
4) blockers of heat shock proteins
5) antagonists of specific signaling pathway proteins
overall idea of rtk inhibition
inhibition of kinase signaling pathways will suppresses of the cell proliferation, differentation, survival, angiogenesis, stimulation of cell death = cancer treatment
how does VEGF contribute to angiogenesis drugs
angiogenesis is mediated through vascular endothelial growth factor (VEGF)
nuclear receptors are classified by location
1) in cytoplasm: steroid hormone receptors
2) nucleus: heterodimeric nuclear receptors
difference between type 1 and type 2 steriod receptors
type 1: inactive receptor is in the CYTOPLASM w chaperone proteins, ligand activation leads to nuclear transolation, binds as homodimers to inverted repeat DNA half sites
type 2: inactive receptor is in NUCLEUS with repressor proteins, ligand LIBERATES receptor, binds as heterodimer with RXR to direct repeat
mechanism of SHR (steroid hormone receptor)
when there is no ligand, SHR are bound to inhibitory (heat shock proteins) which keeps receptor in the cytoplasm
1) ligand binds -> hsps are released
2) once @ nuclear level, the ligand/receptor complex binds unique DNA sequences called hormone response elements, at the gene promotor
3) -> recruits co-activators or co-repressors = can facilitate or inhibit transcription process
mechanisms involve methylation, acetylation, or phosphorylation of histone proteins or dna
steroid hormone receptor regulation
1) histone deacetylases -> represses gene expression
2) histone acetyltransferases -> inc gene expression
classical mode moa
estrogen binds and
activates intracellular estrogen
receptors (ERα, ERβ) -> dimerize in the
nucleus -> bind to estrogen-response
elements in the promoters of target
genes -> regulate transcription
indirect regulation of gene expression moa
interaction of ligand-bound ERs with other TF
binding to membrane receptors ERs or GPR30
and activation of protein kinase cascafes or alterations via 2nd messengers -> by membrane ers: activation of transcription factors that regulate gene expression or -> by GPR30s: rapid non genomics effects (activation of specific enzymes)
ligand- independent manner
ERs are activated and regulate gene expression through phosphorylation in response to GF binding to their membrance receptors
non steroid hormone receptors
are located in the nucleus and under basal state are bound to DNA and are not active bc they are linked to a co-repressor RXR molecule
mech of thyroid receptors
in absence of thyroid hormones, TX-RXR heterodimer associates with a corepressor complex -> binds to a promoter regions of DNA = inhibits gene expression
in presence of TH, corepressor complex dissociates from TR:RXR heterodimer -> coactivators get recruited = gene transcription occurs
selective receptor modulators SRMS
nuclear receptor ligand, are compounds that exert agonistic as well as antagonistic actions in a tissue selective manner
SERMS selective estrogen receptor modulators
compounds that exert estrogenic as well as anti-estrogenic actions in a tissue selective manner
unique PharmaKinetics properties bc its selective
