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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