A non-enzymatic p21 protein inhibitor of stress-activated protein kinases

THE stress-activated protein kinases (SAPKs), which are identical to the c-Jun amino-terminal kinases (JNKs), are activated in response to a variety of cellular stresses, including DNA damage, heat shock or tumour-necrosis factor-α1,2. SAPK, a subfamily of the mitogen-activated protein (MAP) kinases, is a major protein kinase that phosphorylates c-Jun and other transcription factors2–5. SAPK phosphorylation of transcription factors is important in stress-activated signalling cascades1–6. Here we report that the protein p21WAF1/CIP1/Sdil, a DNA-damage-inducible cell-cycle inhibitor7–10, acts as an inhibitor of the SAPK group of mammalian MAP kinases. This highlights a new biochemical activity of p21, which may provide the first evidence for a non-enzymatic inhibitory protein for SAPK. We suggest that p21, by inhibiting SAPK, may participate in regulating signalling cascades that are activated by cellular stresses such as DNA damage.