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Molecular Genetics of p53 Mediated Tumorigenesis and its Potential as a Therapeutic Target

IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata

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Title Molecular Genetics of p53 Mediated Tumorigenesis and its Potential as a Therapeutic Target
Creator Bajaj, Swati
Subject Molecular & Human Genetics
Description Chromosome instability (CIN) is the hallmark of cancer. It has been hypothesized that defects in genes involved in chromosome segregation may lead to CIN by causing aneuploidy. Recent evidences suggest aneuploidy can be both beneficial and detrimental for cellular transformation depending on genetic context. Aneuploidy can result due to defects in Spindle Assembly Checkpoint (SAC), failed Cytokinesis and Centrosome amplification during mitosis. Improper chromosome alignment during metaphase triggers the SAC that arrests initiation of anaphase. An extensive interaction among the SAC proteins and their regulation by phosphorylation and ubiquitination determines whether or not chromosomes will segregate equally into two daughter cells. Recent evidences suggest that altered expression and regulation of SAC genes leads to abnormal mitotic behavior that may result in cellular transformation. p53, the guardian of the genome, has been shown to regulate several checkpoint events however little is known about its control of spindle assembly checkpoint. Unlike most other tumor suppressor genes, p53 exhibit unique changes both at the structural and functional level when mutated. p53 mutations are mostly missense mutations unlike frameshift and nonsense mutations found in other tumor suppressor genes. These mutant proteins are not functionally-defective, rather, they exhibit very distinct and different functions compared to the wild type protein. These mutant p53 proteins have been shown to function as transcription factors, controlling the expression of various genes involved in cellular proliferation. Interestingly, these proteins show altered expression of several cell cycle checkpoint genes in cancer cell lines and primary tumors. This ‘aberrant’ control accounts for enhanced growth observed in mutant tumors than the wild type ones. In our search for spindle assembly checkpoint genes which are under the direct control of p53, we stumbled upon UBE2C. UBE2C is an E2 Ubiquitin- Conjugating enzyme that regulates cell cycle progression through the mitotic phase by ubiquitination of mitotic cyclins. UBE2C is overexpressed in a wide variety of tumors, resulting in a compromised spindle assembly checkpoint and genomic instability.
Date 2010
Type Thesis
Format application/pdf
Identifier http://www.eprints.iicb.res.in/494/1/SWATI_BAJAJ_PHD_THESIS.pdf
Bajaj, Swati (2010) Molecular Genetics of p53 Mediated Tumorigenesis and its Potential as a Therapeutic Target. PhD thesis, Jadavpur University.
Relation http://www.eprints.iicb.res.in/494/