They play important roles as tumor suppressors; their down-regulation causes leukemias and lymphomas in mice [6], [11], [12] and [13]. Ikaros family transcription factors participate in the control of intracellular signaling pathway mediated by B cell receptor (BCR) [14], [15], [16], [17], [18] and [19]. For instance, Ikaros critically regulates the

pre-BCR-mediated cell cycle arrest, and also promotes tumor suppression through its cooperation with downstream molecules of the pre-BCR signaling pathway in acute lymphoblastic leukemia cells [15]. The disruption of Aiolos in mice showed that most splenic B lymphocytes selleck chemicals llc were differentiated to follicular mature B lymphocytes, suggesting that BCR-delivered maturation signals are enhanced [17]. On the other hand, although Helios is constitutively expressed in hematopoietic tissues [9], it is mainly detected in T lymphocytes after differentiation and involved in T lymphocyte development and function [9], [20], [21], [22] and [23]. Helios is also expressed in B lymphocytes [9], [24] and [25], and silencing of Helios is critical for normal

function of B lymphocytes [24]. However, the physiological role including BCR-signaling of Helios in B lymphocytes remains to be elucidated. Gene targeting techniques using chicken immature B cell line DT40 [26] are excellent http://www.selleckchem.com/products/isrib-trans-isomer.html methods to study physiological functions of various genes in immature B lymphocytes [27], [28] and [29]. Concerning study on the BCR-signaling, Ikaros-deficiency in DT40 induced the BCR-signaling defect with reduced phospholipase C-γ2 phosphorylation and impaired 4��8C intracellular calcium mobilization [16]. In addition, disruption of Aiolos in DT40 caused drastic acceleration of the BCR-mediated

apoptosis [18] and [19]. We also revealed that lack of Aiolos accelerated apoptosis mediated by the BCR stimulation through transcriptional regulation of protein kinase Cs (PKCs) and elevation in cytochrome c release [19]. Recently, interestingly, it was reported that Helios is expressed even in DT40 [29]. These results suggest that Helios may also participate in controlling the BCR-signaling pathway of DT40, as well as Ikaros and Aiolos. Therefore, to clarify the function of Helios in the BCR-signaling pathway, we generated and analyzed the Helios-deficient DT40 mutant, Helios−/−. Our results showed that Helios may regulate BCR-mediated apoptosis via controlling gene expression of several PKCs. In immature B lymphocytes, cross-linking of BCR induces their apoptosis, but antigen binding to BCR triggers their activation and proliferation [30] and [31]. Therefore, cross-linking of the BCR in immature B lymphocytes is thought to function as a mechanism to exclude self-reactive B cell clones (negative selection), although the regulation mechanisms of BCR-mediated apoptosis still remain unclear.