and/or frameshift, resulting in loss of p53 expression (loss of protein expression is seen in the case of other mutant tumor suppressors) However, most are missense mutations and many 'cluster' within the DNA binding domain (DBD) with six 'hotspots' being the most frequently substituted. Mutant p53 has an impaired ability to interact with its cognate DNA sequence; nonetheless, it can directly affect gene expression by interacting with other sequence elements or indirectly by interacting with other transcription factors - click to see the structure of a mutant p53 in complex with DNA. In addition, mutant p53 interacts with many other proteins to either promote or inhibit their activity, thus affecting the normal course of many cellular pathway and contributing to metastasis in p53 cancers. Different mutations contribute to distinct cellular events such as invasion and motility, proliferation and growth, genomic instability, cell survival, drug and chemo-resistance. A number of notable interactions of mutant p53 and their consequences are presented. Mutant p53 associates with nuclear factor Y - a transcription factor complex, leading to increased expression of genes involved in proliferation and chemoresistance. Other transcription factors whose target genes are transactivated by mutant p53 include Ets1 and Ets2, the vitamin D receptor (VDR) and sterol regulatory element binding factor Srebf2, the latter leading to increased sterol biosynthesis and tissue remodeling and in mammary cancer, to aberrant tissue morphology. On the other hand, the interaction of Tp63 and 73 - members of the p53 family and tumor suppressor transcription factors, leads to inhibition of their target gene transcription. And not only transcription factors are binding partners for mutant p53. The interaction with Mre11a, a component of the MRN complex involved in DNA damage response and repair (see ATM signaling and homologous recombination (HR) pathway of double strand DNA repair pathways), promotes genetic instability. The interaction with the prolyl isomerase Pin1 leads to a more aggressive transcriptional program and increased migration and invasion of breast cancer cells. Interestingly, some of the above gene products also interact with the wild-type p53, albeit with different, even opposite outcomes. Tumor cell exhibit increased expression and/or amplification Mdm2 and Mdm4 - the two genes that negatively regulate p53 in unstressed cells. The two genes are also reported to have Tp53 independent functions that result is genomic instability, possibly via interactions with MRN complex (the two genes are highlighted green as the results are negative). Many of the post-translational modifications (PMT) of p53 take place outside the DBD; while they likely preserved, the outcomes may be different. The interactions with partners, particularly those that use the DBD, the expression of target genes - protein coding and non-coding, are likely to be affected as well. Wild-type p53 leads to apoptosis and senescence in tumor cells and several therapies are considered to restore the wild-type function. Examples include the use of small molecules that bind to mutant p53 and increase the level of a protein with wild-type conformation and activity or the use of zinc to recover wild-type folding. Other approaches include increasing the turnover of the mutant protein or targeting pathway that the mutant p53 regulates To see the ontology report, for annotations, GViewer and download, click here...(less)