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Distribuzione asimmetrica degli mRNA per proteine ribosomali nel citoplasma
Full text linkmRNA localization is a conserved post-transcriptional process crucial for a variety of systems. We have analyzed the subcellular distribution of mRNAs encoding human cytosolic and mitochondrial ribosomal proteins. Biochemical fractionation experiments showed that the transcripts for cytosolic ribosomal proteins associate preferentially with the cytoskeleton via actin microfilaments. Transfection in HeLa cells of a GFP reporter construct containing the cytosolic ribosomal protein L4 3′-UTR showed that the 3′-UTR is necessary for the association of the transcript to the cytoskeleton. Using confocal analysis we demonstrate that the chimeric transcript is specifically associated with the perinuclear cytoskeleton. We also show that mRNA for mitochondrial ribosomal protein S12 is asymmetrically distributed in the cytoplasm. In fact, this transcript was localized mainly in the proximity of mitochondria, and the localization was 3′-UTR-dependent. In summary, ribosomal protein mRNAs constitute a new class of localized transcripts that share a common localization mechanism
Regulatory role of rpL3 in cell response to nucleolar stress induced by Act D in tumor cells lacking functional p53
No full textMany chemotherapeutic drugs cause nucleolar stress and p53-independent pathways mediating the nucleolar stress response are emerging. Here, we demonstrate that ribosomal stress induced by Actinomycin D (Act D) is associated to the up-regulation of ribosomal protein L3 (rpL3) and its accumulation as ribosome-free form in lung and colon cancer cell lines devoid of p53. Free rpL3 regulates p21 expression at transcriptional and post-translational levels through a molecular mechanism involving extracellular-signal-regulated kinases1/2 (ERK1/2) and mouse double minute-2 homolog (MDM2). Our data reveal that rpL3 participates to cell response acting as a critical regulator of apoptosis and cell migration. It is noteworthy that silencing of rpL3 abolishes the cytotoxic effects of Act D suggesting that the loss of rpL3 makes chemotherapy drugs ineffective while rpL3 overexpression was associated to a strong increase of Act D-mediated inhibition of cell migration. Taking together our results show that the efficacy of Act D chemotherapy depends on rpL3 status revealing new specific targets involved in the molecular pathways activated by Act D in cancers lacking of p53. Hence, the development of treatments aimed at upregulating rpL3 may be beneficial for the treatment of these cancers
5-FU targets reply to induce mitochondrial apoptosis via cystathionine-b-synthase in colon cancer cells lacking p53
No full textRecent findings revealed in cancer cells novel stress response pathways, which in response to many chemotherapeutic drugs causing nucleolar stress, will function independently from tumor protein p53 (p53) and still lead to cell cycle arrest and/or apoptosis. Since it is known that most cancers lack functional p53, it is of great interest to explore these emerging molecular mechanisms. Here, we demonstrate that nucleolar stress induced by 5-fluorouracil (5-FU) in colon cancer cells devoid of p53 leads to the activation of ribosomal protein L3 (rpL3) as proapoptotic factor. rpL3, as ribosome-free form, is a negative regulator of cystathionine-β-synthase (CBS) expression at transcriptional level through a molecular mechanism involving Sp1. The rpL3-CBS association affects CBS stability and, in addition, can trigger CBS translocation into mitochondria. Consequently apoptosis will be induced through the mitochondrial apoptotic cell death pathway characterized by an increased ratio of Bax to Bcl-2, cytochrome c release and subsequent caspase activation. It is noteworthy that silencing of CBS is associated to a strong increase of 5-FU-mediated inhibition of cell migration and proliferation. These data reveal a novel mechanism to accomplish p53- independent apoptosis and suggest a potential therapeutic approach aimed at upregulating rpL3 for treating cancers lacking p53
Distribuzione asimmetrica degli mRNA nel citoplasma
No full textRegolazione post-trascrizionale dell'espressione genica: localizzazione subcellulare degli mRNA di proteine ribosomal
rpL3 mediated the cell response to nucleolar stress induced by ActD in p53 null cancer cells
No full textMany chemotherapeutic drugs impair ribosomal biogenesis causing nucleolar stress and p53-independent pathways mediating the nucleolar stress response are emerging. Here, we demonstrate that nucleolar stress induced by Actinomycin D is associated to the up-regulation of ribosomal protein L3 (rpL3) and its dissociation from the ribosome in lung and colon cancer cell lines lacking p53. We show that rpL3 is involved in drug-induced apoptosis and inhibition of cell proliferation and migration by controlling p21 expression both at transcriptional and post-translational levels. Depletion of rpL3 abolishes the cytotoxic effects of Act D while rpL3 overexpression was associated to a strong increase of Act D-mediated inhibition of cell migration. We identified extracellular-signal-regulated kinases1/2 (ERK1/2) and mouse double minute-2 homolog (MDM2) as new molecular targets involved in rpL3-mediated molecular pathways activated by Act D in cancers lacking of p53. Taking together our results show that the efficacy of Act D chemotherapy depends on rpL3 status. Hence, the development of treatments aimed at upregulating rpL3 may be beneficial for the treatment of these cancer
Meccanismi di splicing alternativo e nonsense mediated mRNA decay (NMD) nella regolazione dell'espressione di geni per proteine ribosomali umane
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Regolazione post-trascrizionale della espressione genica mediante localizzazione di mRNA
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