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A widespread strategy employed by pathogens to establish infection is to inhibit host-cell protein synthesis. Legionella pneumophila, an intracellular bacterial pathogen and the causative organism of Legionnaires' disease, secretes a subset of protein effectors into host cells that inhibit translation elongation. Mechanistic insights into how the bacterium targets translation elongation remain poorly defined. We report here that the Legionella effector SidI functions in an unprecedented way as a transfer-RNA mimic that directly binds to and glycosylates the ribosome. The 3.1 Å cryo-electron microscopy structure of SidI reveals an N-terminal domain with an 'inverted L' shape and surface-charge distribution characteristic of tRNA mimicry, and a C-terminal domain that adopts a glycosyl transferase fold that licenses SidI to utilize GDP-mannose as a sugar precursor. This coupling of tRNA mimicry and enzymatic action endows SidI with the ability to block protein synthesis with a potency comparable to ricin, one of the most powerful toxins known. In Legionella-infected cells, the translational pausing activated by SidI elicits a stress response signature mimicking the ribotoxic stress response, which is activated by elongation inhibitors that induce ribosome collisions. SidI-mediated effects on the ribosome activate the stress kinases ZAKα and p38, which in turn drive an accumulation of the protein activating transcription factor 3 (ATF3). Intriguingly, ATF3 escapes the translation block imposed by SidI, translocates to the nucleus and orchestrates the transcription of stress-inducible genes that promote cell death, revealing a major role for ATF3 in the response to collided ribosome stress. Together, our findings elucidate a novel mechanism by which a pathogenic bacterium employs tRNA mimicry to hijack a ribosome-to-nuclear signalling pathway that regulates cell fate.

The article focuses on the enigmatic role of Fragile X Messenger Ribonucleoprotein (FMRP) in nucleolar localization and its potential functions beyond the cytoplasm. Topics include the structural similarities and differences between FMRP and its related proteins FXR1P and FXR2P, the debate over FMRP's involvement in ribosome biogenesis within the nucleolus, and the implications of these findings for understanding Fragile X Syndrome.

The tumor suppressor p14/19ARF regulates ribosomal RNA (rRNA) synthesis by controlling the nucleolar localization of Transcription Termination Factor 1 (TTF1). However, the role played by TTF1 in regulating the rRNA genes and in potentially controlling growth has remained unclear. We now show that TTF1 expression regulates cell growth by determining the cellular complement of ribosomes. Unexpectedly, it achieves this by acting as a "roadblock" to synthesis of the noncoding LncRNA and pRNA that we show are generated from the "Spacer Promoter" duplications present upstream of the 47S pre‐rRNA promoter on the mouse and human ribosomal RNA genes. Unexpectedly, the endogenous generation of these noncoding RNAs does not induce CpG methylation or gene silencing. Rather, it acts in cis to suppress 47S preinitiation complex formation and hence de novo pre‐rRNA synthesis by a mechanism reminiscent of promoter interference or occlusion. Taken together, our data delineate a pathway from p19ARF to cell growth suppression via the regulation of ribosome biogenesis by noncoding RNAs and validate a key cellular growth law in mammalian cells. [ABSTRACT FROM AUTHOR]

The present study examines the outcomes of a 5-week summer bridge writing program at a Midwestern, urban, public university designed to provide remedial instruction for incoming first-year college students, approximately 500 students annually for 7 years. Regression results showed that program participation was a positive, significant predictor on the outcomes of 6- and 4-year graduation, first-year earned credits, and first-year college grade point average, even after controlling for demographic and academic preparation variables. The combination of academic preparation and an introduction to the college experience helped to prepare students for college success. This institutionally funded program shows promise in addressing the remediation needs of students and preparing them for success in credit-bearing courses as well as college life in general, getting them on track for timely college graduation.

This article presents a control group study of the influence of a partnership-centered, community-based learning program on students' academic writing. The improved writing of first-year students in the Chicago Civic Leadership Certificate Program (CCLCP), we argue, results from the deeply situated learning that took place in the context of reciprocal, community-based relationships. We also argue that research on the impact of community-based learning should take into account the contemporary university's emerging paradigm of engaged learning and research, which calls for a redefinition of partnership and reciprocity. (Contains 5 tables and 4 notes.)

Both MAP-kinase (ERK) phosphorylation and mutations that simulate the phosphorylation decrease the affinity of the individual HMG boxes of the architectural transcription factor UBF for linear ribosomal DNA but have little or no effect on the capacity of these HMG boxes to bind to pre-bent DNA and do not affect the overall binding constant of UBF for the DNA. The data demonstrate that ERK phosphorylation of UBF prevents DNA bending by its first two HMG boxes, leading to a cooperative unfolding of the enhancesome.

During apoptosis, cells are fragmented into sealed packages for safe disposal by phagocytosis, a process requiting major reorganisation of the cytoskeleton. The small p21 GTPase-activated kinases (PAKs) have been implicated in regulating cytoskeletal dynamics and a subset are activated by caspase 3/7 cleavage. However, the functional importance of this activation in apoptosis remains unknown. Using early Xenopus embryos, we have dissected xPAK1 activation from other causative events in apoptosis. An apoptotic-like cell fragmentation was observed 30 min after expression of the xPAK1 catalytic domain and occurred in the absence of other markers of apoptosis. In vitro, activated xPAK1 phosphorylated the regulatory light chain (xMLC) of myosin II at threonine 18 and serine 19, events known to activate the actin-dependent ATPase of cytoskeletal myosin. In vivo, activated xPAK1 induced hyperphosphorylation of xMLC. BDM, a myosin inhibitor, and ML-7, a MLCK inhibitor, both abrogated cell fragmentation induced by activated xPAK1, and ML-7 also inhibited xPAK1 activity. Endogenous xPAK1 was cleaved during normal apoptosis and this was associated with xPAK1 activation and increased serine 19 phosphorylation of xMLC. The data show that PAK activation is sufficient for apoptotic body formation in vivo and strongly suggest that activation of myosin II is essential for this process. Keywords: Apoptosis; Cell fragmentation; xPAK1; Ste20; Myosin II; JNK; Xenopus

The MLK family of mitogen activated protein kinase kinase kinases (MAPKKK) has been shown to activate Jun N-terminal kinase/stress-activated protein kinase 1 (JNK/SAPK1). However, little is known of the in vivo functions of the MLKs. We have identified a Xenopus laevis MLK that shows highest homology with mammalian MLK2 (62%) and, like MLK2, interacts preferentially with the Rho-family GTPase Rac. xMLK2 was expressed zygotically from late gastrula/early neurula. Surprisingly, this expression was restricted to the cement gland, the brain, and the pronephros. In the differentiating cement gland, xMLK2 expression correlated with cell elongation and the onset of a previously unobserved apoptotic phase, while in the pronephros, expression corresponded with the differentiation and opening of the nephric tubules. Overexpression of xMLK2 in COS7 cells led to a SEKI/MKK4 (MAPKK)-dependent hyperactivation of JNK in response to UV irradiation, xMLK2 was shown to be required for normal cement gland development and pronephric tubule formation using antisense inactivation and a dominant negative xMLK2. The data suggest a novel role for the MLKs as tissue-restricted mediators of signal transduction. They also suggest that tissue-specific responses to common extracellular signals may in part result from the programmed expression of MAPKKKs with differing specificities. Keywords: Xenopus; Signal transduction; Cement gland; Pronephros; Programmed cell death; Mixed lineage kinase 2; (MLK2, MST, MAP3K10); JNK/SAPK1

The ribosomal RNA genes of eukaryotic cells have been studied. Results, discussed in this minireview, suggest that they may control important aspects of cell behavior. They are known to encode the enzymatic scaffold of the ribosome and to perform what may be the most basic of all housekeeping functions.