Taken together, it can be postulated that incorporation of cleaved TCTP into apoptosome inhibits etoposide induced apoptosis by preventing recruit ment of procaspase 3 to the apoptosome. In addition, the mechanism how fragmented TCTP that comprises only a small fraction of Apaf 1 binding TCTP in apoptosome enables the protection selleckchem of HeLa cells against etoposide induced toxicity remains to be addressed. It can be inferred that some specific environment might led to posttranslational modification of TCTP possibly at its C terminal. This possibility is supported by prior observations Inhibitors,Modulators,Libraries that N terminal region of TCTP is necessary for its interaction with Bcl xL for its antiapopto tic activity and that extracellular N terminal truncated TCTP exhibits cytokine like activities via its homo dimerization.

Therefore, cleaved form TCTP might contain N terminal region and C terminal fragments that possibly induce changes of ternary structure of TCTP which enable the association Inhibitors,Modulators,Libraries of Apaf 1 in apoptosome complex. This implies that distinctive form of TCTP may exist to separately interact with its different intracellular partners. The structural modification of TCTP including truncation or oligomerization, which may be provoked in specific conditions, appears to be involved in the mechan ism for acquiring its pleiotropic activity. Proteolytic enzymes, such as caspases, which are pref erentially activated upon apoptotic signals, are possibly involved in the C terminal Inhibitors,Modulators,Libraries cleavage of TCTP. However, this possibility can be ruled out since the primary se quence of TCTP does not contain the enzymatic site for caspase activity.

As only S 100 is com Inhibitors,Modulators,Libraries petent to cleave the TCTP, apoptosome formation is not necessary for its cleavage. We tested various kinds of protease inhibitors including VAD, LDESD, DEVD, LEHD, and Inhibitors,Modulators,Libraries MG132 and found that cleavage of TCTP was not prevented by those agents. It is also supported by the evidence that re combinant caspase 3 did not cleave recombinant TCTP in vitro whereas it produces the cleavage of known sub strate PARP. Furthermore, S 100 treated with Apaf 1 domain specific blocking antibodies as well Ca2, followed by TCTP addition, caused the fragmentation of TCTP. How TCTP becomes fragmented and which residues in TCTP are subjected to cleavage are under investigation. Because TCTP is regarded as an oncogene and is up regulated in tumors, reducing the TCTP levels or inhibit ing its activity, are viewed www.selleckchem.com/products/Bosutinib.html as alternative rational approaches in cancer therapy. Recently, the pathophysiological associ ation of high TCTP status with poor prognosis in a large cohort of breast cancer patients was demonstrated. Also, TCTP inactivation by pharmacological compounds has been studied as modalities of cancer therapy.