The Role Of C-Abl In TNF-? Induced PARP-1 Activation And Gene Expression

Poly(ADP-ribose)polymerase(PARP)is a family of 18 different proteins,found in eukaryotes and prokaryotes and they have very different structures and functions in the cell.poly(ADP-ribose)polymerase 1(PARP-1)is the most well established member of the PARP family.It is highly activated by DNA strand breaks and interacts physically and functionally with various proteins,transferring an ADPribosyl moiety from NAD+ to glutamate or aspartate residues of target proteins.It proceeds by the successive transfer and polymerization of ADP riboses(PAR)in the target protein,rapidly creating long branched polymers that are subsequently degraded by poly ADP-ribose glycohydrolase(PARG).PAR may itself,as a covalent attachment of auto modified PARP-1,act to recruit proteins to sites of DNA damage.Roles played by PARP-1 in the cell appear to be significant in establishing cellular complexity.The challenges for this field have to address include how these ubiquitous factors can have so many different functions,the insights of the PARP-1 activation to synthesize the polymer in the absence of DNA damage.In the past decades,studies have extensively addressed the non-DNA damage-induced PARP1 activation as well as its implications in gene expression.Studies have demonstrated that PARP-1 is activated via extracellular signal-regulated kinase(ERK)signaling cascade that mediates growth and differentiation.The findings reveal an alternative mode of PARP-1 activation,which does not involve binding to DNA or DNA damage and phosphorylate PARP-1 leading to activate PARP-1 that regulates PARylation.Non-receptor tyrosine kinases' roles in leukocytes activation have drawn increasing attention.The previous studies in our laboratory have addressed that Abelson(ABL)family of nonreceptor tyrosine kinase c-Abl plays roles in regulating neutrophil adhesion and migration or stimulating pro-inflammatory cytokine expression in T cells.In the present study,we tested whether c-Abl-can regulate PARP-1.Our results showed that TNF alpha stimulation induced the interaction of c-Abl and PARP-1,and resulted in tyrosine phosphorylation and increased catalytic activity of PARP-1.Additionally,the results demonstrate that using c-Abl inhibitor(STI-571)causes inhibition of inflammatory cytokines pathway through inhibition of PARP-1 which suggest that may be used as a drug for the treatment of inflammatory diseases.