SUMMARY
The reprogramming factors that induce pluripotency have been identified primarily from embryonic stem cell (ESC)-enriched, pluripotency-associated factors. Here we report that during mouse somatic cell reprogramming, pluripotency can be induced with lineage specifiers that are pluripotency rivals to suppress ESC identity, most of which are not enriched in ESCs. We found that OCT4 and SOX2, the core regulators of pluripotency, can be replaced by lineage specifiers that are involved in mesendodermal (ME) specification and in ectodermal (ECT) specification, respectively. OCT4 and its substitutes attenuated the elevated expression of a group of ECT genes whereas SOX2 and its substitutes curtailed a group of ME genes during reprogramming. Surprisingly, the two counteracting lineage specifiers can synergistically induce pluripotency in the absence of both OCT4 and SOX2. Our study suggests a “seesaw model,” in which a balance that is established using pluripotency factors and/or counteracting lineage specifiers can facilitate reprogramming.
Calcineurin plays a pivotal role in the T cell receptor (TCR)-mediated signal transduction pathway and serves as a common target for the immunosuppressants FK506 and cyclosporin A. We report the identification of a novel endogenous calcineurin binding protein named Cabin 1 that inhibits calcineurin-mediated signal transduction. The interaction between Cabin 1 and calcineurin is dependent on PKC activation. Overexpression of Cabin 1 or its N-terminal truncation mutants inhibits the transcriptional activation of calcineurin-responsive elements in the interleukin-2 promoter and blocks dephosphorylation of NF-AT upon T cell activation. These results suggest a negative regulatory role for Cabin 1 in calcineurin signaling and provide a possible mechanism of feedback inhibition of TCR signaling through cross-talk between protein kinases and calcineurin.
A new member of the mouse NK family of homeobox genes that is related to Drosophila NK-3 has been identified. Expression of this gene, termed Nkx-3.1, is largely restricted to the prostate gland in adult animals. The level of Nkx-3.1 mRNA decreases markedly in response to castration, suggesting that its expression is androgendependent. In situ hybridization analyses demonstrated that expression of Nkx-3.1 in the prostate is confined to epithelial cells. In newborns, Nkx-3.1 mRNA is detected in the urethral epithelium that is being induced by the surrounding mesenchyme to invaginate to form prostatic buds. Together, these observations suggest that the Nkx-3.1 protein, which likely functions as a transcription factor, plays a prominent role both in the initiation of prostate development and in the maintenance of the differentiated state of prostatic epithelial cells.
Recognition of viral nucleic acids by pattern recognition receptors initiates type I IFN induction and innate antiviral immune response. Here we show that LSm14A, a member of the LSm family involved in RNA processing in the processing bodies, binds to synthetic or viral RNA and DNA and mediates IRF3 activation and IFN-β induction. Knockdown of LSm14A inhibits cytosolic RNA-and DNA-trigger type I IFN production and cellular antiviral response. Moreover, LSm14A is essential for early-phase induction of IFN-β after either RNA or DNA virus infection. We further found that LSm14A-mediated IFN-β induction requires RIG-I-VISA or MITA after RNA or DNA virus infection, respectively, and viral infection causes translocation of LSm14A to peroxisomes, where RIG-I, VISA, and MITA are located. These findings suggest that LSm14A is a sensor for both viral RNA and DNA and plays an important role in initiating IFN-β induction in the early phase of viral infection.
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