regulation of transcription factor II Flashcards
what is tumor hypoxia?
low oxygen tension <1% O2
- increases with increasing distance from capillaries
- activates genes involved in angiogenesis, tumor cell migration and metastasis
what is involved in hypoxia to form new blood vessels?
- VEGF
- PDGF-b
- FGF-3
- endotheline 1 & 2
- angiopoietin-2
- VEGF receptor (FLT-1)
- Nitric oxide synthase 2 (NO)
- heme oxygenase 1 (CO)
what is involved in hypoxia to form red blood cells?
erythropoetin
what is involved in hypoxia for anaerobic glycolysis?
- GLUT 1,3
- hexokinase 1,2
- phosphofructukinase L, C
- aldolase A,C
- triosephosphate isomerase
- GAPDH
- phosphoglycerokinase 1
- enolase 1
- pyruvate kinase M
- lactate dehydrogenase A
- carbonic anhydrases 9,12
what is HIF?
hypoxia inducing factor
what is HIF involved in?
- hormonal regulation
- cytoskeleton formation
- cell proliferation
- vasomotor regulation
- growth and apoptosis
- energy metabolism
- angiogenic signalling
- matrix and barrier functions
- transcriptional regulation
- transport
- virus related
HIF mediates hypoxic response
- TF that regultes hypoxia induced gene transcription
- heterdimer HIF-1a and 1b subunits
- HIF-2a
- HIF-1/2a levels are tightly regulated by O2 and degraded in normoxia but stabilised in hypoxia
HIF subunits
bHLH; basic helix loop helix
PAS; per-arnt-sim
TAD; transactivation domain C-terminus or N terminus
ODD; oxygen dependent degradation domain
normoxia
- 3 proline hydroxylase enzymes (PHDs) in presence of O2 and cofactors hydroxylate HIF
- recognition by von Hippel Lindau (VHL) protein; an E3 ligase which targets HIF for degradation via ubiquitination
hypoxia process
- PHDs inactive, HIF translocates to nucleus
- activates genes involved in angiogenesis, tumor cell migration and metastasis
what are some growth factor mediated pathways?
- insulin
- IGF-1 increase HIF protein synthesis in normoxia
- RTK signalling increased
mTOR
mammalian target of rapamycin
PI3K
phosphoinositide 3 kinase
AKT
protein kinase B
kinase/MAPK
mitogen activated protein kinase
kidney cancer/ RCC
- highly angiogenic tumor
what happens to VHL in RCC?
tumor suppresion protein von Hippel-Lindau (VHL) is mutated in >80% of clear cell RCC
- loss of VHL function leads to expression of TFs hypoxia inducible factor-1 and 2
- HIF-2a is the oncogenic driver
p53 function and regulation
- most frequently altered gene in human cancers
- in normal unstressed cells p53 protein is low
- regulated by MDM2/HDM2 by binding to the N-terminal transactivation domain
- promoting p53 ubiquitination and degradation by E3 ligase activity
list of p53 functions
- hypoxia
- DNA damage
- ribosomal stress
- oncogene activation
- senescence
- genomic stability
- DNA repair
- survival
- cell cycle arrest
- apoptosis
- nutrient deprivation
- telomere erosion
what can p53 help promote?
repair and survival of damaged cells, or it can promote the permanent removal of damaged cells through death or senescence
p53 structure
TD: transactivator domain required for transcriptional activation
PD: poly-proline domain, required for protein-protein interaction
NLS: nuclear localisation signal
OD: oligomerisation domain
R: regulator domain
p53 after DNA damage
increase in p53 levels with increased ability of p53 to bind DNA and mediated transcriptional activation
summary of HIF
HIF activates VEGF pathway and subsequent further downstream cell signalling via RTK
