Cancer

How do cells decide which pathway to use to repair DNA Breaks and what is the impact on cancer?

The DNA Damage Response (DDR) is a major component of a cells defence against disease. It serves to recognize and repair DNA damage, to regulate cell-cycle progression and where necessary, promote programmed cell death. One of the most potentially dangerous forms of DNA damage is a double stranded DNA break (DSB), which must be dealt with to maintain the structural and genetic integrity of a cell. Failure to do so results in generation of chromosomal aberrations such as chromosomal translocations that are potentially tumorigenic.

Control of the cell response to chemotherapy by modulating degradation of p53 protein isoforms

We demonstrated that the p53 tumour suppressor gene expresses at least twelve different p53 proteins due to alternative splicing, alternative initiation of translation and alternative promoter usage. We determined that p53 isoform proteins are expressed in normal human tissue in a tissue dependent manner. P53 isoforms are abnormally expressed in a wide range of cancer and are associated with breast cancer prognosis.

What regulates the alternative splicing of the TP53 gene and how can we take control of it to change cell fate outcome in response to cellular stress?

We demonstrated that the p53 tumour suppressor gene expresses at least twelve different p53 proteins due to alternative splicing, alternative initiation of translation and alternative promoter usage. We determined that p53 isoform proteins are expressed in normal human tissue in a tissue dependent manner. P53 isoforms are abnormally expressed in a wide range of cancer and are associated with breast cancer prognosis.

Inhibition of P53 Tumour Suppressor Function by Metastasis-Associated Mage-A Proteins

MAGE-A (melanoma antigen) proteins comprise a 12-member sub-family of cancer/testis antigens, so called because, physiologically, they are expressed almost exclusively in the testis, but during the development of a range of cancers (including melanoma where they were initially discovered) their expression is re-activated and is tightly associated with malignancy (i.e. with invasion and metastasis). Experimental evidence supports the idea that they are actually drivers of the malignant phenotype.

The spatio-temporal dynamics of induction of the Keap1/Nrf2 pathway

Multicellular organisms are equipped with elaborate networks of cytoprotective proteins (e.g., glutathione transferases, NAD(P)H: quinone oxidoreductase 1, heme oxygenase 1) that defend against the damaging effects of oxidants and electrophiles, the principal contributors to the pathogenesis of chronic diseases. Under basal conditions, these genes whose transcription is dependent on transcription factor Nrf2, are not expressed at their maximum capacity, but can be upregulated (induced) by a variety of synthetic and natural agents (inducers).

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