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G0/G1 switch gene 2 (G0S2) is a basic protein with ill-defined function that inhibits the proliferation of hematopoietic stem cells. Herein, we show that treatment of K562 cells with 5-azacytidine (5-Aza) resulted in a 24-fold increase in G0S2 expression and a reduction in cell growth. Conversely, gene demethylation in the presence of G0S2-specific shRNA restored proliferation, further supporting an inhibitory role for G0S2 in cell proliferation. Elevated levels of G0S2 inhibited the division of K562 cells by sequestering the nucleolar phosphoprotein nucleolin in the cytosol. G0S2 inhibited the proliferation of leukemia cells in vivo in xenograft models. Collectively, our data identify a new mechanism that controls proliferation in K562 cells, suggesting a possible tumor suppressor function in leukemia cells., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The transcription factor Krüppel-like factor 4 (KLF4) can activate or repress gene expression in a cell-context dependent manner. We have previously shown that KLF4 inhibits the proliferation of naïve CD8(+) T cells in vitro downstream of the transcription factor ELF4. In this work, we describe a novel role of KLF4 in the differentiation of CD8(+) T cells upon infection. Loss of KLF4 had minimal effect on thymic T cell development and distribution of mature T cells in the spleen, blood, and lymph nodes. KLF4-deficient naïve CD8(+) T cells also displayed normal homeostatic proliferation upon adoptive transfer into lymphopenic hosts. However, activation of KLF4-deficient naïve CD8(+) T cells by in vitro TCR crosslink and co-stimulation resulted in increased proliferation. Furthermore, naïve KLF4-deficient OT-I CD8(+) T cells generated increased numbers of functional memory CD8(+) T cells compared to wild type OT-I CD8(+) T cells co-injected in the same recipient in both primary and recall responses to Listeria monocytogenes-OVA. Collectively, our data demonstrate that KLF4 regulates differentiation of functional memory CD8(+) T cells while sparing development and homeostasis of naïve CD8(+) T cells., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Transcription factors that regulate the quiescence, proliferation and homing of lymphocytes are critical for effective immune system function. Here we demonstrate that the transcription factor ELF4 directly activated the tumor suppressor KLF4 'downstream' of T cell antigen receptor signaling to induce cell cycle arrest in naive CD8(+) T cells. Elf4- and Klf4-deficient mice accumulated CD8(+)CD44(hi) T cells during steady-state conditions and generated more memory T cells after immunization. The homeostatic population expansion of CD8(+)CD44(hi) T cells in Elf4-null mice resulted in a redistribution of cells to nonlymphoid tissue because of lower expression of the transcription factor KLF2 and the surface proteins CCR7 and CD62L. Our work describes the combinatorial effect of lymphocyte-intrinsic factors on the homeostasis, activation and homing of T cells.

Highlights: [•] KLF4 has minimal role in the development and homeostatic proliferation of CD8+ T cells. [•] KLF4 restrains proliferation of CD8+ T cells in response to in vitro TCR stimulation. [•] Loss of KLF4 augments development of CD8+ T cell memory after Listeria infection. [ABSTRACT FROM AUTHOR]