The cellular function of the cancer-associated RNA-binding protein La has been linked to translation of viral and cellular mRNAs. Recently, we have shown that the human La protein stimulates IRES-mediated translation of the cooperative oncogene CCND1 in cervical cancer cells. However, there is little known about the underlying molecular mechanism by which La stimulates CCND1 IRES-mediated translation, and we propose that its RNA chaperone activity is required. Herein, we show that La binds close to the CCND1 start codon and demonstrate that La's RNA chaperone activity can change the folding of its binding site. We map the RNA chaperone domain (RCD) within the C-terminal region of La in close proximity to a novel AKT phosphorylation site (T389). Phosphorylation at T389 by AKT-1 strongly impairs its RNA chaperone activity. Furthermore, we demonstrate that the RCD as well as T389 is required to stimulate CCND1 IRES-mediated translation in cells. In summary, we provide a model whereby a novel interplay between RNA-binding, RNA chaperoning and AKT phosphorylation of La protein regulates CCND1 IRES-mediated translation.

Up-regulation of anti-apoptotic factors is a critical mechanism of cancer cell resistance and often counteracts the success of chemotherapeutic treatment. Herein, we identified the cancer-associated RNA-binding protein La as novel factor contributing to cisplatin resistance. Our data demonstrate that depletion of the RNA-binding protein La in head and neck squamous cell carcinoma cells (HNSCC) increases the sensitivity toward cisplatin-induced cell death paralleled by reduced expression of the anti-apoptotic factor Bcl2. Furthermore, it is shown that transient expression of Bcl2 in La-depleted cells protects against cisplatin-induced cell death. By dissecting the underlying mechanism we report herein, that the La protein is required for Bcl2 protein synthesis in cisplatin-treated cells. The RNA chaperone La binds in close proximity to the authentic translation start site and unwinds a secondary structure embedding the authentic AUG. Altogether, our data support a novel model, whereby cancer-associated La protein contributes to cisplatin resistance by stimulating the translation of anti-apoptotic factor Bcl2 in HNSCC cells.

Pediatric chronic critical illness (PCCI) is characterized by prolonged and recurrent hospitalizations, multiorgan conditions, and use of medical technology. Our prior work explored the mismatch between intensive care unit (ICU) acute care models and the chronic needs of patients with PCCI. The objective of this study was to examine whether the number and frequency of treatment weans in ICU care were associated with clinical setbacks and/or length of stay for patients with PCCI. A retrospective chart review of the electronic medical record for 300 pediatric patients with PCCI was performed at the neonatal intensive care unit, pediatric intensive care unit, and cardiac intensive care unit of two urban children's hospitals. Daily patient care data related to weans and setbacks were collected for each ICU day. Data were analyzed using multilevel mixed multiple logistic regression analysis and a multilevel mixed Poisson regression. The patient-week level adjusted regression analysis revealed a strong correlation between weans and setbacks: three or more weekly weans yielded an odds ratio of 3.35 (95% confidence interval [CI] = 2.06–5.44) of having one or more weekly setback. There was also a correlation between weans and length of stay, three or more weekly weans were associated with an incidence rate ratio of 1.09 (95% CI = 1.06–1.12). Long-stay pediatric ICU patients had more clinical setbacks and longer hospitalizations if they had more than two treatment weans per week. This suggests that patients with PCCI may benefit from a slower pace of care than is traditionally used in the ICU. Future research to explore the causative nature of the correlation is needed to improve the care of such challenging patients.

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