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The role of VHL in kidney cancer - Coggle Diagram
The role of VHL in kidney cancer
VHL
pseudohypoxia
process wherein cells express hypoxia associated proteins regardless of oxygen status
common in tumors
Von hIppel Lindau Protein
2 forms
VHL30
VHL19
expressed in all cells
substrate conferring component of the VHL-elongin B-elongin C (VBC)
the part of the protein complex that recognises and binds to hydroxylated HIF1/2a
cannot bind to unhydroxylated HIF
VBC: group of proteins that work together to form an E3 umbiquitin ligase
the complex that decorates HIF with ubiquitin
what happens when a protein is polyubiquitinated?
polyumbiquitination acts as a destroy signal
polyubiquitinated HIF is degraded by the 26s proteosome
apart from Hypoxia VHL bindings sometimes doesn't occur in mutation
VHL disease
Kidney Cancer
clear cell renal cell carcinoma (ccRCC)
VHL and ccRCC
sporadic ccRCC has high rates if VHL loss or mutation
in almost all sporadic (not associated with VHL disease) ccRCC cases , VHL is lost or mutated (approx. 90%)
no other gene is perturbed to these levels in ccRCC
HIF stabilising after VHL loss or mutation promotes ccRCC
VHL is technically tumor suppressor gene
HIF2a promotes tumor growth
theories
HIF1a promotes early stages of tumorigenesis but is redundant in the later stages where HIF2a takes over
HIF1a is a tumor supressor whereas HIF2a is an oncogene
HIF1a vs HIF2a
HIF2a promotes ccRCC
HIF1a appears to decrease the rate of ccRCC tumor growth
compared to control
bind to hypoxia response elements
VHL loss/mutation and HIF2a stabilization
promotes the hallmarks of cancer
promtoes expression of genes that promote ccRCC
TGF alpha: proliferation
GAL3ST1: metastasis
cyclin D1-proliferation
Plin2: dysregulation of cell metabolism, increased lipid droplets
VEGF-angiogenesis
targeting of HIF2a in ccRCC
HIF1a inhibitors
belzutifan
people with VHL disease also get ccRCC
Subtypes
usually only one kidney effected
renal cell carcinoma (85%)
clear cell renal cell carcinoma is the most common type of renal cell carcinomas (75%)
named for its histological appearance - cytoplasm appears clear, this is due to an accumulation of glycogen and lipids
as the tumor grows it effects kidney function an can cause symptoms such as:
painful spasms in your kidney or bladder or a dull side pain
high temperatures and night sweats
a lump in your kidney area
tiredness and weight loss
blood in urine