Transcript BMP Receptor 1 : Juvenile Polyposis (Colon Cancer)

BMP Receptor 1 :
Juvenile Polyposis
(Colon Cancer)
Cecily Johnson
Biology 169
March 24, 2005
Juvenile Polyposis Syndrome

What is JPS?

A neoplastic (proliferative)
vascular disorder.

Predisposes individuals to
gatrointestinal cancers.
Source: http://www.gihealth....on/photo/colonPolyps.html
How is it inherited?



JPS can occur in an individual
by a brand new gene change.
By a gene change that is
inherit from a parent (at least
half of reported cases).
JPS is inherited in an
autosomal dominant fashion.
All contents copyright © 1992-2004 the Author(s) and The University of Iowa. All rights
reserved.
http://www.vh.org/pediatric/patient/cancercenter/juvenilepolyposis/inherited.ht
ml
How is it
Related to
cancer?
Class notes
TGF-Beta Pathway
Normal Function of TGF-Beta
Pathway:


Pathway product
(SMAD4) binds to
DNA in the nucleus
and regulates
transcription of target
genes.
Very important in
majority of body cells

In cardiovascular
development, and
remodeling and growth
control of body cells.
Nature Reviews: Genetics,FROM DEVELOPMENTAL DISORDER
TO HERITABLE CANCER: IT’S ALL IN THE BMP/TGF-β FAMILY,
Kristin A.Waite* and Charis Eng*‡§. October 2003 Volume 4
BMP Specific Functions

Important in cell
differentiation

Regulate
proliferation,
and apoptosis
Nature Reviews: Genetics,FROM DEVELOPMENTAL DISORDER
TO HERITABLE CANCER: IT’S ALL IN THE BMP/TGF-β FAMILY,
Kristin A.Waite* and Charis Eng*‡§. October 2003 Volume 4
BMPR1A

Activation of this receptor by the Type II receptors results
in activation of the R-SMADs. (Just another step in the
pathway)

JPS individuals with BMPR1A mutations have 10 or
more gastrointestinal tract polyps and a family history of
gastrointestinal cancer.
Mutations in BMPR1A

Inherited Cancers:

Associated with 50% of JPS cases.

Mutations are frequent in the ligand-binding domain
and the kinase domain, resulting in a loss of ligand
binding or loss of kinase activity.

Truncating mutations.
Nature Reviews: Genetics,FROM DEVELOPMENTAL DISORDER
TO HERITABLE CANCER: IT’S ALL IN THE BMP/TGF-β FAMILY,
Kristin A.Waite* and Charis Eng*‡§. October 2003 Volume 4
Mutations in BMPR1A

Non-inherited Cancers:

Associated with 50% of JPS individuals.

Due to large deletions and rearrangements or
promoter mutations in one of the genes.

Other reasons could be due in part to mutations in one
of the other Transformation Growth Factor-Beta
Pathway members.
Knock Out

Null mutations of Bmpr1a are lethal to mice
embryos.

Generated mice in which Bmpr1a could be
conditionally inactivated for study.
Knock Out: Results


Disruption of
homeostasis of
intestinal epithelial
regeneration.
Eventually leading to
intestinal polyposis
much like those in
human JPS.
http://www.iecdesmoines.com/images/polyp2.jpg
More Knock Out Results


In wild-type mice,
proliferation cells
are located in the
upper crypt region.
In mutant mice, the
proliferating cell
population was
expanded.
ANY QUESTIONS?