P53 Gene Therapy
The p53-protein is a tumour suppressor and one of the most important controlling distances for cell growth. As such, it is also one of the central topics of oncological research.
The tumour-suppressing gene of the same name, p53, is located on chromosome 1703.1.
Its molecular weight is 53 kDa (thus the name). Its half-life is approximately 0 to thirty minutes. The intracellular concentration increases significantly if DNA damage occurs. In genomically inconspicuous cells, the p53-protein is found inactivated and bound to its inhibitor, HD11.2 (humand-double-minute-chromo-some2 gene).
New Research papers published by Saisei Mirai
Functions and potential of the latest p53 gene therapy
With the new liposomal-based p53 gene therapy, seven times more therapeutic genes are introduced into the DNA without any side effects.
The p53-protein plays a central part in the expression of genes contributing to the regulation of apoptosis and DNA repair. In 1992, it was declared “Guardian Angel of the Genome”, and in 1993 it was made “Molecule of the Year”.
P53-Protein is activated via phosphorylation by the enzyme ATM-Kinase (ataxia telangiectasia mutated kinase) which is induced during DNA-damaging stimuli such as UV Light. Through phosphorylation, the p53-protein is transformed into its confirmation state so that HMD-2 can be diffused and only activated p53 remains. This process guarantees that protein levels stay constant and can be raised quickly if need be.
The p53-protein is being ubiquitinated constantly by Mdm2-ubiquitiniligase. The protein is being rebuilt all the time and has a half-life of 20 to 30 minutes.
The p53-protein can interrupt the cell cycle and thus stop the proliferation of a genomically suspicious or damaged cell. As a result, cells have more time to repair themselves, or in case of mistakes that cannot be corrected, initiate programmed cell death.
The interruption of the cell division can occur in the G1-Phase, i.e. before the restriction point. Here, p53 induces the expression of protein p21 which inhibits the D-Cyclin/CDK4/6-Complex – which is independent from growth rate – and the Cylin E/CDK2-Complex which is a trigger of the transition between the GO-Phase and the G1-Phase.
An arrest of cell division can also occur after a faulty or incomplete replication of a genome (in the 5-phase) during the G2-Phase. In this case, p53 prevents the forming of the B-cyclin/CDK1-complex which is essential for starting a cell’s mitosis phase.
In extreme cases, inducing the BAX-protein of the BCL2-family starts apoptosis.
A mutation of the genes is evident in about 60 per cent of all tumour-based diseases. This is important since a genetically damaged and potentially malicious cell is unable to enter apoptosis in order to destroy itself. Patients with p53-mutation respond poorly to for instance chemotherapy since the genomically damaged cells that form here cannot be eliminated through the p53-pathway and apoptosis. They can continue to proliferate and, in the worst case, even metastasize. The defective p53-protein is not the cause of cancer but the body’s inability to prevent cell damage and malicious growth at an early stage. Tumour-based diseases caused by p53-mutation are adrenocortical carcinoma, esophagus carcinoma and nasopharynx carcinoma, e.g..
New approaches in cancer therapy research consist of creating a “molecular prosthesis” for mutated defunct p53-protein. Prominent representatives are CP-31398 and PRIMA-1/APR-246 which have caused rapid tumour cell death through the restoration of p53-functionality in knockout-mice with lymphoma and sarcoma. APR-246 binds covalently to the cystein rest in the core of the p53-protein which restores normal confirmation and function. This approach is more tumour specific than conventional chemo-therapy and appears to have fewer side effects.