Differential modulation of cyclin‐dependent kinase inhibitor p27Kip1 by negative signaling via the antigen receptor of B cells and positive signaling via CD40

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Abstract
The cross‐linking of surface immunoglobulins (sIg) of B cells can transmit a negative signal, resulting in cell cycle arrest, apoptosis or both. Signaling via the B cell antigen CD40 reverses the sIg‐mediated negative signaling and induces activation and proliferation of B cells. We investigated the molecular mechanisms for cell cycle regulation by negative and positive signaling via sIg and CD40, respectively, by using the B cell line WEHI‐231. Cross‐linking of sIg almost completely reduced the activity of cyclin‐dependent kinase (Cdk) 2, essential for cell cycle progression in the late G1 phase, although the level of Cdk2 was not reduced. Among the factors that regulate Cdk2 activation, the activity of the Cdk‐activating kinase (CAK) appeared intact and cyclin E was reduced only partially in sIg‐cross‐linked WEHI‐231. In contrast, sIg cross‐linking induced a significant Cdk inhibitor (CKI) activity. Since a 27‐kDa protein was co‐precipitated with Cdk2 in anti‐Ig‐treated, but not untreated WEHI‐231, and the CKI activity in anti‐Ig‐treated WEHI‐231 was neutralized by anti‐p27Kip1, antibodies, it is most likely that p27Kip1 is responsible for the CKI activity induced by sIg cross‐linking. p27Kip1 may thus play a role in growth inhibition of B cells by negative signaling via sIg. In contrast, CD40 signaling enhanced Cdk2 activity and reduced the p27Kip1 level in anti‐Ig‐treated WEHI‐231, suggesting that the reduction of p27Kip1 plays an important role in the abrogation of sIg‐mediated growth arrest by CD40 signaling. Taken together, p27Kip1 is likely to be a crucial target molecule of the negative signaling via sIg and the positive signaling via CD40 essential for T cell‐dependent immune responses.