Transcript p57 & Beckwith-Weidemann Syndrome

p57
&
Beckwith-Weidemann
Syndrome
Claire Conn
Outline
Normal Function of p57
Beckwith-Weidemann Syndrome
Relationship of p57 to cancer
The Role of p57 in the
Cell
Remember CDKs?
 Cyclin-CDK complexes
are important
regulators of the cell
cycle
 They are regulated in 3
ways:
 Synthesis of cyclins
 Phosphorylation – both
inhibitory and
stimulatory
 CDK inhibitory proteins
(CKIs)
CKIs
 INK4 Family (p16 family)
 Inhibitors of CDK4
 Selectively inhibit only
CDK4/6
 p16INK4a, p15INK4b, p18INK4c,
p19INK4d
 Cip/Kip Family (p21
family)
 CDK interacting
protein/Kinase inhibitory
protein
 Inhibit any of the cyclinCDK complexes
 p21Cip1, p27Kip1, p57Kip2
p21
CDK
Cycli
n
CDK4
Cyclin
CDK
Cyclin
p16
CDK4
p16
p21
CKIs
Cip/Kip Inhibitors
active
CDK
Cyclin
+
p21
 Inhibit cyclin-CDK
inactive
complexes by
CDK
inhibiting kinase
p21
activity by blocking
Cyclin
ATP.
 All are candidates as
tumor suppressor
genes
p27Kip1
Cyclin A
CDK2
Jeffrey et al. (1995) Nature 376:313
CDK2
Cyclin A
Russo et al. (1996) Nature 382:325
Why do we need 3 of them?
 Redundancy
 Variation in response and activity
 p21 is induced by p53 to mediate G1 arrest in response to
DNA damage
 p27 is induced by cell-cell contact to mediate contact
inhibition
 p57 is involved in early development especially
organogenesis
Knock-out Mice
p57
 Has an effect on cells to exit the cell cycle
 Not all the defects are linked to cellular proliferation
suggesting it has other roles than as a CKI
 Genomically imprinted with the maternal allele being
preferentially expressed in most tissues
 Found on chromosome 11 in a cluster of imprinted genes
(including IGF-2)
 High expression during embryogenesis and decreases to
low levels in adulthood
Imprinting
Imprinting and Cancer
Imprinting and Cancer
Beckwith-Wiedemann
Syndrome
BWS
 Congenital
overgrowth disorder
causing large body
size and large organs.
 Usually sporadic but
may be inherited.
 Multigenic disorder
 Increased rate of
tumor development
Clinical Characteristics
 Macroglossia
 Large, protruding
eyes
 Abdominal wall
defects
Umbilical hernia
Omphalocele
 Pitted Ear lobes
 Hypoglycemia
 Heart defects
 Cleft palate
 Enlarged organs
Kidney, liver, spleen
Associated Tumors
Wilms Tumor
Hepatoblastoma
Neuroblastoma
Rhabdomyosarcoma
Etiology
 Dysregulation of alleles in the chromosome
region 11p15.5
Treatment
Most treatment involves treating the
symptoms
IV solutions for hypoglycemia
Surgery to remove congenital tumors
Surgery to reduce tongue size to obtain an
open airway
Periodic screenings for evidence of associated
tumors
The Role of p57 in
BWS/Cancer
p57 and Cancer
 Maternal allele loss of
p57 is involved with
some cases of BWS
as well as a variety of
tumors
 In BWS mutations
were found in the
CDK binding domain
and the nuclear
localizing region
p57 and BWS
 p57 knockout mice
have a lot of
overlapping
symptoms with BWS
 Only ~5% of BWS
cases have a
mutation in p57
 Other mechanisms for
silencing p57 and/or
other genes are
involved with the
development of BWS
Possible causes for BWS
Loss of imprinting of IGF-2
Loss of function of p57
Trisomy with paternal duplication
Maternally inherited translocations
p57 and IGF-2
Double mutant study
Found characteristics of BWS not seen in
other mouse models
BWS symptoms more severe than in
either single mutant
Review
p57 is a CKI that is genomically imprinted
and functions mostly during embryonic
development regulating organogenesis
BWS is a congenital overgrowth disorder
p57 is a tumor suppressor and loss of
function results in increased proliferation
References
Caspary, Tamara et al. “Oppositely imprinted genes p57kip2 and Igf2
interact in a mouse model for Beckwith-Wiedemann Syndrome.”
Genes and Development 13 (1999): 3115-3124.
Gaston, V. et al. “Gene Mutation in Beckwith-Wiedemann Syndrome.”
Hormone Research 54 (2000): 1-5.
Hatada, I. et al. “New p57 mutations in Beckwith-Wiedemann
Syndrome.” Human Genetics 100 (1997): 681-683.
Jirtle, Randy L., Jennifer Weidman. “Imprinted and more equal.”
American Scientist 95 (2007): 143-149
Mainprize, Todd G. et al. “Cip/Kip cell-cycle inhibitors: A neurooncological perspective.” Journal of Neuro-Oncology 51 (2001): 205218.
Nakayama, Kei-ichi, Keiko Nakayama. “Cip/Kip cyclin-dependent
kinase inhibitors: brakes of the cell cycle engine during
development.” BioEssays 20.12 (1998): 1020-1029.
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Questions