Molecular Genetics of p53 Mediated Tumorigenesis and its Potential as a Therapeutic Target
IR@IICB: CSIR-Indian Institute of Chemical Biology, KolkataView Archive Info
Molecular Genetics of p53 Mediated
Tumorigenesis and its Potential as a
Molecular & Human Genetics
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.
Bajaj, Swati (2010) Molecular Genetics of p53 Mediated Tumorigenesis and its Potential as a Therapeutic Target. PhD thesis, Jadavpur University.