LIGHT, a member of the TNF superfamily, activates Stat3 mediated by NIK pathway.
Stat3, a member of the signal transducers and activators of transcription (STAT) family, is a key signal transduction protein activated by numerous cytokines, growth factors, and oncoproteins that controls cell proliferation, differentiation, development, survival, and inflammation. Constitutive activation of Stat3 has been found frequently in a wide variety of human tumors and induces cellular transformation and tumor formation. In this study, we demonstrated that LIGHT, a member of tumor necrosis factor superfamily, activates Stat3 in cancer cells. LIGHT induces dose-dependent activation of Stat3 by phosphorylation at both the tyrosine 705 and serine 727 residues. The activation of Stat3 by LIGHT appears to be mediated by NIK phosphorylation. Expression of a kinase-inactive NIK mutant abolished LIGHT induced Stat3 activation. Overexpression of an active NIK induces Stat3 activation by phosphorylation at the both tyrosine 705 and serine 727 residues. Activation of Stat3 by NIK requires NIK kinase activity as showed by kinase assays. In addition, LIGHT increases the expression of Stat3 target genes including cyclin D1, survivin, and Bcl-xL, and stimulates human LNCaP prostate cancer cell growth in vitro which can be blocked by expression of a dominant-negative Stat3 mutant. Taken together, these results indicate that in addition to activating NF-kappaB/p52, LIGHT also activates Stat3. Activation of Stat3 together with activating non-canonical NF-kappaB/p52 signaling by LIGHT may maximize its effects on cellular proliferation, survival, and inflammation.
Nadiminty
Nagalakshmi
N
Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Chun
Jae Yeon
JY
Hu
Yan
Y
Dutt
Smitha
S
Lin
Xin
X
Gao
Allen C
AC
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D013997:Time Factors; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000378:metabolism* / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014443:Tyrosine / Q000737:chemistry; D000097782:NF-kappaB-Inducing Kinase
D016207:Cytokines; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D050796:STAT3 Transcription Factor; D012694:Serine; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha; D014443:Tyrosine; D000097782:NF-kappaB-Inducing Kinase; C494086:STAT3 protein, human; C505914:TNFSF14 protein, human