Translationally controlled Tumor Protein (TCTP) is an evolutionally highly conserved protein which has been implicated in many cellular functions that are related to cell growth, death, and even the allergic response of the host. To address the physiological roles of TCTP, we generated TCTP knockout mice by targeted gene disruption. Heterozygous mutants appeared to be developmentally normal. However, homozygous mutants (TCTP ؊/؊ ) were embryonic lethal. TCTP ؊/؊ embryos were smaller in size than the control littermates at all postimplantation stages examined. Although TCTP is widely expressed in both extraembryonic and embryonic tissues, the most prominent defect of the TCTP ؊/؊ embryo at embryonic stage day 5.5 (E5.5) was in its epiblast, which had a reduced number of cells compared with wild-type controls. The knockout embryos also suffered a higher incidence of apoptosis in epiblast starting about E6.5 and subsequently died around E9.5-10.5 with a severely disorganized structure. Last, we demonstrated that TCTP ؊/؊ and control mouse embryonic fibroblasts manifested similar proliferation activities and apoptotic sensitivities to various death stimuli. Taken together, our results suggest that despite that TCTP is widely expressed in many tissues or cell types, it appears to regulate cell proliferation and survival in a tissue-or cell type-specific manner.

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Translationally controlled tumor protein (TCTP) is expressed throughout T cell development and prominently induced following T cell activation. However, its function(s) during these processes is unclear. Here, we demonstrated that conditional deletion of TCTP before the β selection checkpoint resulted into a partial block of thymocyte development at the double-negative (DN) 3 stage. Deletion of TCTP in the double-positive (DP) stage did not cause any significant phenotype in the thymus except a slight increase of mature CD8 single-positive (SP) thymocytes. In contrast to the very modest phenotype observed in the thymus, a significant reduction of mature T cells was observed in the peripheral lymphoid organs of these two conditional null TCTP mutant mice. Detailed analysis revealed that the latter phenotype (peripheral T cell lymphopenia) was largely due to a decreased viability of mature TCTP-deficient (TCTP−/−) T cells. Transgenic expression of the anti-apoptotic protein Bcl-2 rescued the partial block of early thymocyte development, but not peripheral T cell lymphopenia of T-lineage-specific TCTP−/− mice, suggesting that the signaling networks of TCTP in these two processes are not identical. Last, we demonstrated that TCTP−/− T cells manifested a significant defect in T cell Ag receptor (TCR)-mediated cell proliferation. Further analysis revealed that such defect was due to a marked delay in the initial cell-cycle entry of TCTP−/− T cells following TCR stimulation. Together, these results indicate that TCTP plays a very modest role in thymocyte development, but is critical for peripheral T cell maintenance and TCR-mediated cell proliferation.

Mcl-1 plays an apical role in many cell survival programs. Mice without Mcl-1 die at early embryonic stage. A conditional knockout approach has thus been employed to study Mcl-1 functions in the liver. Mice without Mcl-1 in hepatocytes (Alb-Mcl-1 −/−) were viable but manifested some defects in the mature liver, including enlarged cell size, enhanced apoptosis and proliferation of liver cells. An increased level of p53 was also observed in adult Alb-Mcl-1 −/− mouse livers. We thus generated Alb-Mcl-1 −/− mice in p53-deficient background to examine whether p53 was involved in Mcl-1 deficiency-induced hepatocyte apoptosis. Loss of p53 in Alb-Mcl-1 −/− mice (DKO mice) resulted in a very high frequency of neonatal death. Further analysis revealed that such early lethality was likely due to hepatic failure caused by a marked reduction of fully-differentiated hepatocytes at the perinatal/neonatal stage. On the other hand, those DKO mice that did survive to adulthood manifested much more severe liver cell damage than Alb-Mcl-1 −/−mice of the same age, suggesting that p53 is activated in Alb-Mcl-1 −/− livers to help resolve Mcl-1 deficiency-induced hepatocyte damage. Last, we demonstrated that p53 enhanced-hepatocyte survival is a cell-autonomous effect, and that such effect is mediated in part through transcriptional up-regulation of p21 Waf1/Cip1 in Alb-Mcl-1 −/− livers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B17.