Two arms of TGFβ signaling

Cancer-associated overproliferation is thwarted in many cell types by transforming growth factor β (TGFβ), which turns on p21(WAF1/CIP1) cell cycle inhibitors via Smad transcription factors. On page 979, Sakaguchi et al. show that TGFβ's arsenal in its antiproliferation crusade is larger than just the Smads—a calcium-binding protein called S100C/A11 also responds to the call of duty.

The group previously showed that high extracellular Ca²⁺ results in phosphorylation of cytoplasmic S100C/A11, driving it into the nucleus. Once there, it releases the transcription factor Sp1 from its binding partner, nucleolin, so that Sp1 can activate p21(WAF1/CIP1) transcription to halt division in skin cells.

The new results demonstrate that this S100C/A11 pathway requires PKCα-mediated phosphorylation of S100C/A11 and, like the Smad pathway, is triggered by TGFβ. Both branches are needed to stop skin cell...