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von Hippel-Lindau (VHL) disease proposal

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Cha, Xer
Morta, Jujen
VHL gene expression in Breast Tissue of pre-pregnant, pregnant and post
pregnant mice with VHL mutant gene
INTRODUCTION:
In the United States, one person of 32,000 people is affected by von Hippel-
Lindau (VHL) disease. Of these affected individuals, forty percent develop renal cell
carcinoma and fifteen percent of patients develop neuroendocrine tumors in the
pancreas, which behaves as if it were a cancer.
2
These are two of the many
effects of VHL.
von Hippel-Lindau (VHL) disease is an inherited, autosomal dominant cancer
syndrome which causes benign and malignant tumors, including: hemangioblastomas in
the central nervous system, pheochromocytomas, adenomas, renal carcinomas, and
papillary cystadenomas of the epididymis (low sperm count in males).
1,2
The VHL
gene is a tumor suppressor gene and located on chromosome 3p25.
3
The disease
is activated upon mutation of the gene. Patients who have the disease originally inherit
one altered copy from their parents and are heterozygous for VHL. When a patient’s
allele becomes altered to homozygous for VHL, abnormal growth of cells occur which
increases the chance of various cancers.
2
There is a rare exception to this fact,
20% of VHL disease patients result from de novo mutation and do not have a family
history.
When individuals have the VHL disease, they are referred to as genetic
“mosaics” for VHL because the body is composed of cells that either contain wildtype
VHL, homozygous for VHL or heterozygous for VHL.
2
1

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Cha, Xer
Morta, Jujen
Identification of the VHL gene occurred through positional cloning (reverse
genetics) and mutations were first identified in the germline of patients.
1,4
Mutation
in the germline of VHL is the cause for inheritance, because germ cells contain only one
copy of VHL.
5
The VHL gene encodes a protein known as pVHL, which acts in a protein
complex with elongin B, elongin C, and cullin-2.
5
This complex possesses ubiquitin
ligase E3 activity for degradation of hypoxia-inducible-factor (HIF-1), which is a
transcription factor that regulates gene expression with oxygen.
5
When an allele of
VHL is mutated, absence of pVHL causes HIF to build up and results in high amounts of
transcription of HIF-monitored genes.
1
This elevated amount of transcription is the
cause of benign and malignant tumor formation in VHL patients. Furthermore, HIF-1
plays a crucial role in angiogenesis of tumors and mammalian development.
HIF-1 is made up of two subunits. It always consists of HIF-1-beta and of one of
the three, HIF-1-alpha, HIF-2-alpha, or HIF-3-alpha.
9
Depending on the what HIF-
1 is made up of, it has transcriptional activator has a different function. Under hypoxic
conditions, HIF-1 is stable and acts as a master regulator. It regulates genes related to
angiogenesis, cell proliferation/survival and glucose/iron metabolism.
9
pVHL only
degrades HIF-1 when consisted of subunits HIF-1-beta and HIF-1-alpha under normal
oxygen conditions.
9
Essentially, the blockade of HIF-1 via pVHL is control cell
growth.
Currently, there is limited information about VHL’s true function, but VHL is
thought to also have a role in induction of cell differentiation.
1
pVHL has been
shown to prohibit renal cell differentiation, without affecting cell cycling and plays a role
2

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Cha, Xer
Morta, Jujen
in neuronal differentiation.
1
Furthermore, it has also been shown that VHL
influences the activity of hematopoietic stem cells in mice.
8
As reported, the areas
VHL mostly affects includes the eye, lower part of the brain, spine, pancreas, adrenal
glands and kidneys.
6
Recent discoveries revealed VHL gene contributing to breast
cancer.
3
In an experiment conducted by Mohammad K. Zia (2007), VHL exerted inhibitory
effects on the invasive and migratory capacity of breast cancer cells in vitro.
3
It was
shown that low levels of VHL occur in aggressive breast tumours and concluded to VHL
acting as a powerful putative tumour suppressor gene in human breast cancer.
3
Until this finding, the VHL tumour suppressor gene was believed not to be involved in
sporadic human breast cancer.
7
Many model organisms have been used to study VHL including, Caenorhabditis
elegans, Drosophila melanogaster, Zebrafish, and mice.
8
An ortholog of VHL
exists in each model organism. Of these model organisms, mice mimic human VHL
disease hallmarks (tumor formation) most closely. The problem with mice is that they
can only exists as heterozygous VHL mutants and die in utero if homozygous because
of abnormalities in the placenta.
1
As a result, Wenbin Ma (2013), created a human
beta-actin promoter-driven cre transgenic mouse that expresses cre in a mosaic pattern
in multiple organs, which is now being used as the leading model organism to study
VHL.
1
3

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