Given our current understanding of the way they are suppressed by normal activity of P53, the aurora Kinase inhibitors should be used in cancers where P53 is clearly dys-regulated, and probably in disease with positive Prostate Stem Cell Antigen. This open the door to Sarcomas (chondrosarcoma being the most cited) and Pancreatic cancers (as well as Bladder cancers).
GADD45, a P53 dependent protein that inhibits Cdc2/Cyclin B1 could therefore be the best predictor of Aurora activity.
Quantification of CDCA8/Borealin, BIRC5/survivin, and INCENP may provide additional information on AURORA KINASE ACTIVITY. Like the core Binding Factor, these 3 Molecules form the Chromosomal Passenger Complex (CPC) which interact with POGZ, EVI5, and JTB.
Niehrs at al further define the role of GADD45 as "Gadd45 recruits nucleotide and/or base excision repair factors to gene-specific loci and acts as an adapter between repair factors and chromatin, thereby creating a nexus between epigenetics and DNA repair." Therefore explaining how P53 induced arrest is followed by DNA repair through recruitment of GADD45. When the cell is trying to repair itself with increase in GADD45, of course it wont want to die, therefore over-expression of GADD45 decrease the c-JUN, protecting therefore from TNF induced apoptosis. GADD45 is not good theoretically when you use Cisplatin or radiation for that matter!
*POGZ explains Nuclear transposition of P53 effects as it impacts SP1, a transcription factor with inteaction of all major playors in the cell including E2F1, POU2F1. YOU TARGET SP1 WITH WITH AFERIN FOR EXAMPLE, IT IS IMPOSSIBLE TO COME UP EMPTY HANDED.
"Identification of Rab11 as a small GTPase binding protein for the Evi5 oncogene"
|Jumping translocation breakpoint|
|RNA expression pattern|
|Jumping translocation breakpoint protein (JTB)|
The JTB family of proteins contains several jumping translocation breakpoint proteins or JTBs. Jumping translocation (JT) is an unbalanced translocation that comprises amplified chromosomal segments jumping to various telomeres. JTB has been found to fuse with the telomeric repeats of acceptor telomeres in a case of JT. Homo sapiens JTB (hJTB) encodes a transmembrane protein that is highly conserved among divergent eukaryotic species. JT results in a hJTB truncation, which potentially produces an hJTB product devoid of the transmembrane domain. hJTB is located in a gene-rich region at 1q21, called EDC (Epidermal Differentiation Complex). JTB has also been implicated in prostatic carcinomas.
KANOME ET AL SUGGESTED
"JTB-induced clustering of mitochondria around the nuclear periphery and swelling of each mitochondrion. In those mitochondria, membrane potential, as monitored with a JC-1 probe, was significantly reduced. Coinciding with these changes in mitochondria, JTB retarded the growth of the cells and conferred resistance to TGF-1-induced apoptosis. These activities were dependent on the N-terminal processing and induced by wild-type JTB but not by a mutant resistant to cleavage. These findings raised the possibility that aberration of JTB in structure or expression induced neoplastic changes in cells through dysfunction of mitochondria leading to deregulated cell growth and/or death."
ONCE AGAIN YOU SEE HOW THE CELL PLAYS, USING SIMPLE THINGS THAT GET COMPLICATED REALLY QUICK!