The La protein is an essential RNA-binding protein implicated in different aspects of RNA metabolism. Herein, we report that small interfering (siRNA)-mediated La depletion reduces cell proliferation of different cell lines concomitant with a reduction in cyclin D1 (CCND1) protein. To exclude off-target effects we demonstrate that exogenous La expression in La-depleted cells restores cell proliferation and CCND1 protein levels. In contrast, proliferation of immortalized CCND1 knockout cells is not affected by La depletion, supporting a functional coherence between La, CCND1 and proliferation. Furthermore, we document by reversible in vivo crosslinking and ribonucleoprotein (RNP) immunoprecipitation an association of the La protein with CCND1 messengerRNA and that CCND1 internal ribosome entry site (IRES)-dependent translation is modulated by La protein level within the cell. In addition, we show elevated La protein expression in cervical cancer tissue and its correlation with aberrant CCND1 protein levels in cervical tumor tissue lysates. In conclusion, this study establishes a role of La in cell proliferation and CCND1 expression and demonstrates for the first time an overexpression of the RNA-binding protein La in solid tumors.
Purpose: Overexpression of eIF4E in surgical margins of head and neck cancer patients is an independent risk factor for recurrence. We hypothesize that overexpressed eIF4E is functionally active in tumor margins through activation of the Akt/mammalian target of rapamycin (mTOR) pathway Experimental Design: Western blots and/or immunohistochemistry were performed to determine whether phosphorylation of mTOR and activation of its downstream molecules eIF4E-binding protein-1 (4E-BP1) and p70 S6 kinase and the upstream modulator of mTOR, Akt, were expressed in margins overexpressing eIF4E.Results: There was a significant association between phospho-4E-BP1 and eIF4E expression of a margin or a significant difference in phospho-4E-BP1 expression between the eIF4E-positive and -negative margins (P < 0.01). A significant association between eIF4E and phospho-p70 S6 kinase as well as eIF4E and phospho-mTOR was also noted (P < 0.05). Western blot analysis indicated a highly significant difference in the phosphorylation status of 4E-BP1 between tumors and resection margins. A total of 89% of the 4E-BP1-expressing margins expressed more of the phosphorylated (, ␥, and ␦) isoforms, whereas 81% of the 4E-BP1-expressing tumors expressed more of the unphosphorylated ␣ isoform. A similar difference in Akt activation was noted between eIF4E-positive margins and tumors (P < 0.05).Conclusions: Overexpression of eIF4E is functionally active in tumor margins through activation of the Akt/ mTOR signaling pathway. The greater degree of expression of downstream targets and upstream regulators of mTOR in margins compared with the tumors indicates preferential activation of the Akt/mTOR signaling pathway in margins overexpressing eIF4E. Rapamycin analogs can potentially be used as adjuvant therapy for patients with eIF4E-positive margins.
Accessible summary• This report describes how abdominal massage was provided to five children, to see if it would help with their constipation. • Children and adults with learning disabilities often have long-term constipation that is treated with laxatives. • The abdominal massage was not effective for all the children.• However the parents enjoyed doing the massage and all thought that it was a helpful and enjoyable experience for them and their children.
SummaryChronic constipation is a common problem in people with learning disabilities. Treatment often involves dietary changes or long-term laxative use. The aim of this study was to examine the effectiveness of abdominal massage. The participants were five children with profound learning disabilities and additional physical difficulties. Their long-standing idiopathic constipation was managed by laxatives. Intervention lasted up to 35 weeks, during which participants received 20 min of massage at least twice daily. Parents were asked to maintain stable use of laxatives during the intervention phase, although some chose to withdraw laxatives during abdominal massage intervention. Abdominal massage appeared to result in stools of a more 'normal' consistency in some cases. However, no significant differences were found in stool frequency. Parents reported that abdominal massage was a positive experience. In addition, they believed that massage was an effective treatment for constipation. As a result, laxative use was reduced in some cases, apparently with no ill-effects. These subjective beliefs were not, however, generally borne out by the objective results.
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