Nemo-like kinase is critical for p53 stabilization and function in response to DNA damage

Abstract

The DNA damage response (DDR) acts as a protective mechanism for maintaining cell homeostasis. Nemo-like kinase (NLK) is a serine/threonine-protein kinase that has an important role in many pathways; however, its function in the DDR has not yet been defined. In our study, NLK-deficient HCT116 cells were found to be resistant to etoposide-induced cell death. We demonstrated that NLK is required for p53 activation in response to DNA damage. Remarkably, mechanistic studies revealed that NLK interacts with p53 and stabilizes p53 by blocking MDM2-mediated p53 ubiquitination and degradation. Furthermore, NLK enhances p53 activity and affects expression downstream of p53. Interestingly, these functions of NLK are not related to its kinase activity. Consistent with these results, NLK-deficient cells have a resistance effect on DNA damage. Therefore, these findings emphasize that NLK is a novel factor in DDR mechanisms.

Integrin α5β1 and p53 convergent pathways in the control of anti-apoptotic proteins PEA-15 and survivin in high-grade glioma

“…We propose that this integrin may be integrated in the growing list of molecular determinants of the p53 tumorsuppressor activity. [61][62][63] Response to chemotherapy may be hindered by p53-mediated cell cycle arrest or senescence. 64,65 As shown here, functional inhibition of the α5β1 integrin may represent a new way to sensitize glioma cells to the p53-dependent proapoptotic effect of Nutlin-3a.…”

Stabilization of ATF5 by TAK1–Nemo-Like Kinase Critically Regulates the Interleukin-1β-Stimulated C/EBP Signaling Pathway

“…In response to these cascades, NLK phosphorylates several transcription factors, including STAT3, Lef-1, and c-Myb. Previously, we have shown that NLK plays a role in the DDR via p53 regulation (7). We also found that NLK negatively regulates nuclear factor kappa B (NF-B) activity by disrupting the interaction between the TAK1 complex and IB kinase ␤ (IKK-␤) (8).…”

“…Plasmids expressing NLK and its mutants with the indicated tags were previously described (7). Mammalian expression plasmids containing Flag-ATF5 and its mutants were generated by cloning into pCDNA5/FRT/TO-Flag; HA-ATF5 and HA-luciferase (HA-Luc) were generated by cloning into pCDNA5/FRT/TO-HA.…”

“…N emo-like kinase (NLK), an evolutionarily conserved mitogen-activated protein kinase (MAPK)-related serine/threonine kinase, plays crucial roles in embryonic patterning, development, inflammation, and the DNA damage response (DDR) by modulating multiple signaling pathways (1)(2)(3)(4)(5)(6)(7). Several reports have suggested that NLK functions downstream of transforming growth factor ␤ (TGF-␤)-activated kinase 1 (TAK1), which is activated by TGF-␤, Wnt, and interleukin-6 (IL-6) signaling (1)(2)(3)(4)(5)(6).…”

Amino-terminal residues of ΔNp63, mutated in ectodermal dysplasia, are required for its transcriptional activity

“…Despite so many years, many questions remain still open in order to fully understand the biological role and function of this transcription factor. This complexity raise from different angles, including for example its stability and degradation [32,33], its connection to micro-RNA [34,35] or its splicing isoforms [36,37]. In keeping with the progress in understanding p53 biology, significant progress is also under way on its potential therapeutic application [38,39].…”