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P73
Shatil Amin
March 27th 2003
..Content
I. Structure and Function
II. Regulation
III. Is it involved in human cancers?
Early Findings
• Related to p53 tumor suppressor family
• Activated by DNA damage
• Mediates GI/S cell cycle arrest and apoptosis
• p73 is a transcription factor
– Target genes: BAX  apoptosis
WAF1(p21)  Cell cycle arrest
DNA damage
p73
Growth Arrest
Apoptosis
TARGET GENES
P21
BAX
TP73 gene  many different
mRnas
• TP73 gene produces 2 classes of isoforms:
– TAp73 isoform (transcriptionally active ,
apoptotic/growth inhibitory activity)
– ∆Np73 isoform
• ∆Np73 isoform lacks transcriptional activity
– Amino truncated
– Controlled by alternate promoter in the same
gene
Promoter 1  TAp73 isoforms (transcriptionally active…antiapoptotic
and growth inhibitory activity)
Promoter 2  Np73 isoforms (NO transcriptional activity)
TP73 gene
One gene, but two different proteins under the control of two
distinct promoters
∆Np73 isoform is a dominant
negative regulator of p53/TAp73
• Inhibits p53 and p73
– Competition for binding
– Oligimerization
• Oncogenic properties !!
• p53 and TAp73 activate Np73
 Dominant negative feedback loop
How does
NAp73 inhibit
p53 and TAp73?
-Oligimerization
-Competition for binding
sites
Tight regulation via
dominant negative
feedback loop!
**One gene: 2 products that are functionally antagonistic**
Involvement in Cancer?
• Ip36 locus commonly deleted in tumors
– Is p73 a tumor suppressor ?
• Tp73 mutations rare in human primary tumors
– Fewer than .5%
• Tp73 knockout mice don’t produce tumors
So…this evidence suggests it’s not a classical tumor
suppressor
Complications in assessing the
role of p73 in tumorigenesis
• Tp73 encodes two functionally opposing proteins:
– An in vitro tumor suppressor (TAp73) and a putative
oncogene (∆Np73)
• Mutations may affect both TAp73 and ∆Np73
together
– Deletions
• Abrogate both in vitro growth inhibitory and
oncogenic activity…..(no net effect!)
• Need to discriminate between TAp73 and ∆Np73
isoforms !!
Experiments that Discriminate
between TAp73 and ∆Np73
Variants of ∆Np73 (with anti-apoptotic activity)
overexpressed in breast cancer cell lines, ovarian
cancer, vulval cancer, and neuroblastic tumors
Used RTPCR
Np73
isoform
Ng SW et.al
• ∆Np73 expression strong adverse prognostic
indicator in Neuroblastoma
– No Np73 expression = 80% survival
– Overexpress Np73 = none survived
• ∆Np73 function (blocking p53 and TAp73
mediated apoptosis) is key to development of
tumor
• Mutation/inactivation of entire gene does not
necessarily lead to cancer
• TA:∆N ratio is what may be altered in cancer !
– Regulating respective promoters (mythylation)
Review of Main Points
• Tp73 gene: two functionally different proteins
– TAp73: stimulates apoptosis and cell cycle arrest in
response to DNA damage
– ∆Nap73: negative regulator of p53 and TAp73 with
oncogenic properties
• Enhanced expression of Np73 form associated
with cancer
• Future Research: assessing TA:Np73 ratios in
cancer