P53 function

Figure 2. Regulation of p53 function by acetylation / deacetylation Under stresses conditions p53 gets phosphorylated, acetylated and consequently gets stabilized. Acetylated p53 has enhanced...

Banerjee S, Kumar BRP, Kundu TK (2004) General transcriptional coactivator PC4 activates p53 function.Mol Cell Biol 24(5) 2052-2062... 

Anthoney DA, Mcllwrath AJ, Gallagher WM, Edlin ARM, Brown R. Microsatellite instability, apoptosis and loss of p53 function in drug resistant tumor cells. Cancer Res 1996 56 1374—1381. 

With loss of p53 function, p2lWAF1/CIP1 is no longer upregulated and is unable to help cells escape from their state of mitotic arrest. 

Wild-type p53 will downregulate the levels of microtubule associated protein 4 (MAIM) so that, when p53 function is absent, the high levels of MAP-4 will stabilize microtubules and sensitize cells to paclitaxel therapy. 

Wahl AF, Donaldson KL, Fairchild C, et al. Loss of normal p53 function confers sensitization to Taxol by increasing G2/M arrest and apoptosis. Nature Med 1996 2 72-79. 

Shao RG, Cao CX, Shimizu T, et al. Abrogation of an S-phase checkpoint and potentiation of camptothecin cytotoxicity by 7-hydroxystaurosporine (UCN-01) in human cancer cell lines, possibly influenced by p53 function. Cancer Res 1997 57 4029 -035. 

B) Deletion of a p53 inhibitory protein will be selective for tumors that have lost p53 function. 

The MDM2 protein is recognized as another important control element of p53 function. The MDM protein was first identified as an oncoprotein that negatively regulates p53 function. The regulatory function is performed within a network that includes the inhibitor pl9 (Fig. 14.10). 

The regulatory network of the MDM2-p53 interaction highlights that loss of the p53 function can occm by several pathways ... 

Fig. 15.10. Pathways of DNA damage-mediated and p53-mediated apoptosis The presence of DNA lesions activates the ATM kinase and leads to an increase in p53 concentration. In a transcription-dependent pathway, p53 functions as a transcription activator of the bax gene. The increase in Bax protein facilitates release of cytochrome C from mitochondria and this serves as a trigger for activation of initiator and effector caspases. p53 also influences apoptosis by less well characterized ways, some of which are transcription independent.

Dorigo, O., Turla, S.T., Lebedeva, S. and Gjerset, R.A. (1998) Sensitization of rat glioblastoma multiforme to cisplatin in vivo following restoration of wild-type p53 function. J. Neurosurg., 88, 535-540. 

Recently, we established that 7-hydroxystaurosporine (UCN-01) is 100,000 fold more potent than caffeine at overcoming the G2 arrest, and dramatically enhances the cytotoxicity of cisplatin in Chinese hamster ovary cells at exactly the same concentrations that bypass the G2 checkpoint [41] [42]. UCN-01 also enhanced the activity of cisplatin in human cell lines, and furthermore, this occurred preferentially in cells with disrupted p53 function [43]. Toxicology experiments have shown that the required doses of UCN-01 are well tolerated in both mice and dogs [44]. Accordingly, UCN-01 would appear to have great potential to be used effectively in combination with cisplatin to enhance cell killing specifically in the tumor. The importance of this strategy for the current discussion is that it emphasizes the... 

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