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  • Furthermore Survivin is a member of

    2021-05-11

    Furthermore, Survivin is a member of the inhibitor of apoptosis family. IR induces a rapid nuclear accumulation of survivin and subsequent phosphorylation of the protein in the nucleus. Co-immunoprecipitation and immunofluorescence co-localization analyses revealed an interaction among survivin, Ku70, γ-H2AX, MDC1, and DNA-PKcs. SiRNA knock down of survivin resulted in an impaired DNA double strand break repair. Furthermore, siRNA knock down of surviving hampered S2056 autophosphorylation of DNA-PKcs and significantly decreased DNA-PKcs kinase activity [104].
    The emerging role of DNA-PK in the homeostasis of cell proliferation Besides the important roles of DNA-PK in DNA repair, radiation sensitivity and inflammatory response, Sul group has demonstrated that DNA-PK is involved in the transcriptional regulation of lipogenic genes during fasting/feeding too [99]. However, these regulations only occur in certain type of cell, so it's still mysterious why DNA-PK is so abundant in all mammalian cells. Contact inhibition is the natural process of arresting cell growth when two or more BAY 41-2272 come into contact with each other. In different tissues or organs, same or different type of cells are in contact and cooperate with each other; and most of them (>95%) are quiescent (at the G0 stage of cell cycle) due to contact inhibition. Contact inhibition induces senescence or apoptosis in primary cell in in vitro cultures. Cancer cells were thought to lack contact inhibition; however their proliferation could also be controlled when cancer cells present in low serum levels or when in contact with neighboring cells (i.e. contact inhibition), which suggest cell contact won't induce apoptosis in cancer cells, but decreases its proliferation. Our recent data have demonstrated that high cell density does decrease the proliferation rate in both primary cell and glioblastoma cells (Fig. 3A), but triggers apoptotic signaling only in primary cells, not in glioblastoma cells. However, little is known about the mechanism of how cell contact regulates cell proliferation. DNA-PKcs were reported long time ago to be inactivated and cleaved into the p250 and p160 bands in vitro when purified DNA-PKcs were incubated with the apoptotic cell extracts [105]. This cleavage was also seen during apoptosis induced by the etoposide, the staurosporine or the Fas antibody. Caspase 1 and caspase 3 were thought to be the enzyme mediating this cleavage [106], [107] through the in vitro protease assay; however, DNA-PKcs was cleaved in caspase-1 and caspase 3-deficient MCF7 cell [108], which indicated caspase 1/3 is dispensable for DNA-PKcs cleavage. Our data also showed that DNA-PKcs could be cleaved into two fragments in both primary cells and glioblastoma cells at high density. Although the high cell density-induced apoptosis of primary cells could result from the activation of caspase 1/3, the high cell density-induced DNA-PKcs cleavage did not require the activation of caspase 3 (Fig. 3B). Moreover, the inhibition of Caspase 3 by caspase-specific inhibitory peptide Z-DEVD-fmk, which prevented staurosporine-induced apoptosis of MCF-7 cells [108], did not affect the cleavage of DNA-PKcs (Fig. 3B), which is consistent with the data from Porter group [108]. These observations indicate high cell density-induced DNA-PKcs cleavage is independent of caspase 1/3 activation; in other words, caspase 1/3 are not necessary in high cell density-induced DNA-PKcs cleavage, which may be regulated by another signaling pathway(s). Beyond how DNA-PKcs is cleaved, the function of the P250 or the p160 may be more interesting to be explored. However, little is known about the roles of these cleaved fragments of DNA-PKcs in cell proliferation or cell division. The above data has demonstrated that the high cell density inhibits cell proliferation due to contact inhibition. PKB/Akt is conserved from rimitive metazoans to humans, and is a serine/threonine kinase with well-characterized functions in a number of essential cellular processes, such as transcription, growth, proliferation and survival [109]. DNA-PK directly activates both PKB and Akt through phosphorylation. DNA-PK is a major Ser 473 kinase of Akt [93], and also required for CpG-DNA-induced activation of Akt [110]. In addition, PKB phosphorylates Akt too, the three PKB isoforms, PKBa, PKBb and PKBg (Akt1, Akt2 and Akt3, respectively) share high amino acid sequence homology [111]. Up to now, over 50 proteins have been identified as putative PKB substrates, all these signals contribute to cell growth, metabolism and survival [112]. So, it's possible that the C-terminal fragment of DNA-PKcs containing kinase domain may relocate into cytoplasm, and regulate the homeostasis of cell proliferation through the phosphorylation and activation of PKB/Akt enzymes although the detail mechanism is not yet uncovered.