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ETOC: Ribosome synthesis is a multistep process initiated in the nucleolus with the transcription of a precursor rRNA that is subjected to a series of modification and processing steps to generate the mature rRNA. In this paper, we describe a novel 60S ribosome biogenesis complex associating with LAS1L that controls rRNA processing and synthesis of the 28S rRNA.

The p27 tumor suppressor negatively regulates G 1 cell cycle progression. However, human malignancies rarely select for deletion/inactivation of p27, a hallmark of tumor suppressor genes. Instead, p27 is degraded or relocalized to the cytoplasm in aggressive malignancies, supporting the notion that p27 sequestration from its nuclear cyclin:cyclin-dependent kinase (cdk) targets is critical. However, emerging cell biology data suggest a novel cdk-independent cytoplasmic function of p27 in cell migration. Here, we find cytoplasmic p27 in 70% of invasive and metastatic melanomas. In contrast, no cytoplasmic p27 was detected in noninvasive, basement membraneconfined melanoma in situ, suggesting a late oncogenic role for cytoplasmic p27 in metastasis. Targeted cytoplasmic expression of wild-type or non-cdk-binding p27 at subphysiologic levels induced melanoma motility and resulted in numerous metastases to lymph node, lung, and peritoneum. These observations point to a prominent role of cytoplasmic p27 in metastatic disease that is independent of cyclin:cdk regulation or mere nuclear loss. [Cancer Res 2007;67(19):9238-43]

Ribosome biogenesis is a highly regulated process ensuring that cell growth (increase in biomass) is coordinated with cell proliferation. The formation of eukaryotic ribosomes is a multistep process initiated by the transcription and processing of rRNA in the nucleolus. Concomitant with this, several preribosomal particles, which transiently associate with numerous nonribosomal factors before mature 60S and 40S subunits are formed and exported in the cytoplasm, are generated. Here we identify Las1L as a previously uncharacterized nucleolar protein required for ribosome biogenesis. Depletion of Las1L causes inhibition of cell proliferation characterized by a G 1 arrest dependent on the tumor suppressor p53. Moreover, we demonstrate that Las1L is crucial for ribosome biogenesis and that depletion of Las1L leads to inhibition of rRNA processing and failure to synthesize the mature 28S rRNA. Taken together, our data demonstrate that Las1L is essential for cell proliferation and biogenesis of the 60S ribosomal subunit.Cell growth (increase in cell mass) and cell division must be coordinated during proliferation for cells to remain at a constant size (13). Biogenesis of eukaryotic ribosomes is a finely tuned process ensuring that the protein synthesis capacity of a cell meets the demands of growth associated with proliferation (31). Ribosome biogenesis is initiated by the transcription of rRNA by RNA polymerase I (Pol I) (28S, 18S, and 5.8S rRNA) in the nucleolus and by RNA polymerase III (5S rRNA) in the nucleoplasm. After undergoing cotranscriptional site-specific modification, the 47S pre-rRNA transcript is submitted to a series of endonucleolytic cleavages and exonucleolytic digestion steps to remove internal and external transcribed spacer (ITS and ETS) regions and generate the mature 18S, 28S, and 5.8S rRNAs (21,26,27,36). Mature rRNAs are then assembled with ribosomal proteins to form the 40S (18S rRNA) and 60S (28S, 5.8S, and 5S rRNA) ribosomal particles. These steps involve a large assortment of factors in addition to the RNA and protein components of the ribosome itself. More than 200 additional accessory proteins and noncoding small RNAs engage in complex reactions of processing, assembly, and nuclear export to generate functional cytoplasmic 40S and 60S subunits (36). Although a large collection of evolutionarily conserved proteins has been implicated in processing and assembly of ribonucleoproteins, many details of these pathways and the precise function of several of these factors remain unresolved (28, 54).Perturbation of rRNA transcription or rRNA processing or deletion of ribosomal proteins has been shown to induce nucleolar stress and stabilization of the tumor suppressor p53 (4, 9-11, 16, 23, 25, 32, 58, 61, 62). It was previously demonstrated that, following nucleolar stress, several ribosomal proteins can bind to HDM2 (an E3 ubiquitin ligase) and inhibit its ability to ubiquitinate and target p53 for degradation, leading to accumulation of p53 and subsequent G 1 cell cycle arrest. This suggests t...

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