The nucleolus: reviewing oldies to have new understandings

Lo, Szecheng J.; Lee, Chi-Chang; Lai, Huey-Jen

doi:10.1038/sj.cr.7310070

Cited by 64 publications

(56 citation statements)

References 62 publications

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“…Recent studies suggest that the nucleolus not only functions as the site for ribosome synthesis, but also has a key role in cell stress sensing. For example, under stress conditions, mammalian cells increase the level of tumor suppressor, p53, which leads to inhibition of Pol I transcription and altered nucleolus morphology (35)(36)(37). Although this work was not focused on the functional consequences of this structural arrangement, it is likely that the application of antifungal peptoids led to this, or similar phenomena, suggesting that these mechanisms are suitable for therapeutic targeting.…”

Section: Discussionmentioning

confidence: 99%

Soft X-ray tomography of phenotypic switching and the cellular response to antifungal peptoids in Candida albicans

Uchida

McDermott

Wetzler

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

141

114

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The opportunistic pathogen Candida albicans can undergo phenotypic switching between a benign, unicellular phenotype and an invasive, multicellular form that causes candidiasis. Increasingly, strains of Candida are becoming resistant to antifungal drugs, making the treatment of candidiasis difficult, especially in immunocompromised or critically ill patients. Consequently, there is a pressing need to develop new drugs that circumvent fungal drugresistance mechanisms. In this work we used soft X-ray tomography to image the subcellular changes that occur as a consequence of both phenotypic switching and of treating C. albicans with antifungal peptoids, a class of candidate therapeutics unaffected by drug resistance mechanisms. Peptoid treatment suppressed formation of the pathogenic hyphal phenotype and resulted in striking changes in cell and organelle morphology, most dramatically in the nucleus and nucleolus, and in the number, size, and location of lipidic bodies. In particular, peptoid treatment was seen to cause the inclusion of lipidic bodies into the nucleus.

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Section: Discussionmentioning

confidence: 99%

Soft X-ray tomography of phenotypic switching and the cellular response to antifungal peptoids in Candida albicans

Uchida

McDermott

Wetzler

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

141

114

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“…30 Through its involvement in rDNA transcription, its association with nascent pre-rRNA, and its assembly and transport of ribosomal particles, nucleolin is believed to assist with every step of ribosome biosynthesis. 31 The transcriptional and ribosome assembly functions of nucleolin have been known for many years. However, the past half-life, by interacting with the UTRs of target mRNAs.…”

Section: Introductionmentioning

confidence: 99%

RNA-binding protein nucleolin in disease

2012

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“…Together with ribosomal proteins and the assistance of multiple processing factors, these rRNAs are assembled into ribosomal subunits (13)(14)(15)(16)(17). Other functions have been ascribed to the nucleolus as well, including the assembly of signal recognition particle, the coordination of stress responses, virus replication, and the control of cell cycle progression and apoptosis (reviewed in Refs.…”

mentioning

confidence: 99%

Nucleolar Targeting of the Chaperone Hsc70 Is Regulated by Stress, Cell Signaling, and a Composite Targeting Signal Which Is Controlled by Autoinhibition

Bański

Mahboubi

Kodiha

et al. 2010

Journal of Biological Chemistry

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Hsc70s are constitutively synthesized members of the 70-kDa chaperone family; they are essential for viability and conserved among all organisms. When eukaryotic cells recover from stress, hsc70s accumulate in nucleoli by an unknown mechanism. Our studies were undertaken to characterize the signaling events and the targeting sequence required to concentrate hsc70 in the nucleoli of human cells. Here, we show that pharmacological inhibitors of phosphatidylinositol (PI) 3-kinase and MEK kinases as well as protein-tyrosine phosphatases abolished the stress-dependent nucleolar accumulation of hsc70. Furthermore, to identify the hsc70 nucleolar targeting sequence, green fluorescent protein-tagged fusion proteins with defined segments of hsc70 were generated and their subcellular distribution was analyzed in growing cells. These studies demonstrated that residues 225 to 297 serve as a heat-inducible nucleolar targeting signal. This segment directs green fluorescent protein to nucleoli in response to stress, but fails to do so under nonstress conditions. Fine mapping of the nucleolar targeting signal revealed that it has two separable functions. First, residues 225 to 262 direct reporter proteins constitutively to nucleoli, even without stress. Second, segment 263 to 287 functions as an autoinhibitory element that prevents hsc70 from concentrating in nucleoli when cells are not stressed. Taken together, PI 3-kinase and MEK kinase signaling as well as tyrosine dephosphorylation are essential for the accumulation of hsc70 in nucleoli of stressed cells. This process relies on a stress-dependent composite targeting signal that combines multiple functions.Heat shock cognate proteins 70 (hsc70) 4 are members of the 70-kDa family of chaperones, which are conserved among all organisms. Unlike cytoplasmic hsp70s, hsc70s are constitutively synthesized and essential for cell survival (1). Hsp/hsc70s are involved in a large number of cellular processes: they contribute to the proper folding of nascent polypeptides, refolding of denatured proteins, and targeting of damaged proteins to the proteasome (reviewed in Refs. 2-4). Hsp/hsc70s are essential for protein sorting to organelles and play a protective role in many human diseases and pathophysiologies, including Alzheimer and Huntington disease or ischemia of the heart and brain (reviewed in Refs. 5 and 6). Furthermore, defects in chaperone function have been linked to human disease and aging (5, 7-9).Members of the hsp/hsc70 family are organized into three domains; the 44-kDa N-terminal ATPase domain is followed by a protein binding segment of 18 kDa and a 10-kDa variable domain at the C-terminal end (reviewed in Ref. 3). Under normal growth conditions, hsc70s shuttle between the nucleus and the cytoplasm; however, hsc70s shuttling is inhibited upon stress (10). Following heat shock, hsc70s initially accumulate in the nucleoplasm, where they associate with chaperone substrates that require refolding (10, 11). When cells recover from stress, hsc70s transiently concentrate in nuc...

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The nucleolus: reviewing oldies to have new understandings

Cited by 64 publications

References 62 publications

Soft X-ray tomography of phenotypic switching and the cellular response to antifungal peptoids in Candida albicans

Soft X-ray tomography of phenotypic switching and the cellular response to antifungal peptoids in Candida albicans

RNA-binding protein nucleolin in disease

Nucleolar Targeting of the Chaperone Hsc70 Is Regulated by Stress, Cell Signaling, and a Composite Targeting Signal Which Is Controlled by Autoinhibition

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