کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2119624 1546805 2010 14 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
CREBBP Re-arrangements affect protein function and lead to aberrant neuronal differentiation
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی تحقیقات سرطان
پیش نمایش صفحه اول مقاله
CREBBP Re-arrangements affect protein function and lead to aberrant neuronal differentiation
چکیده انگلیسی

Biallelic inactivation of the CREB-binding protein (CREBBP) a transcriptional co-activator produces an embryonic lethal phenotype in mice. In humans, re-arrangements in CREBBP are associated with the Rubinstein–Taybi Syndrome (RSTS) that is characterised by craniofacial, skeletal and neuronal symptoms. Neuronal defects in RSTS can be attributed to genetic re-arrangements in CREBBP, which has been implicated in synaptic plasticity and long-term memory. The present study was designed to investigate the role of CREBBP re-arrangements during neuronal differentiation. Towards this, deletion constructs of pCREBBP, viz. pΔCB–HAT and pΔHAT–CT were generated and transfected into NT2 cells. Expression profiling of the components of Notch, Wnt, SHH and Retinoid signaling along with screening of the neuronal markers was carried out in the NT2 cells and their mutant derivatives. ChIP-PCRs along with co-immunoprecipitations were also performed in these cells to investigate defects due to inappropriate interaction of mutated CREEBP with the corresponding transcription factor and other transcription regulatory proteins both at steady state as well as during differentiation. Mutant NT2 cells lacking the CREB, BROMO and HAT domains (CB–HAT) were highly proliferative and showed limited differentiation; while mutant NT2 cells expressing CREBBP lacking the HAT and CTAD domains (HAT–CT) are proliferation deficient and differentiate rapidly albeit generating an insufficient number of neurons. Altered CREBBP structure resulted in changes in HAT activity, cell cycle profiles and expression of basal levels of components of Notch, SHH, Wnt and retinoid pathways known to be critical in the proliferation and differentiation of neuronal progenitors. At the chromatin level, aberrant signaling correlated with altered binding affinities of the (CREBBP—transcription factor) complexes to promoter regions of components of these pathways. Thus, differentiation defects are manifested early at the genomic level leading to aberrant transcription of the genes involved in differentiation along the neuronal lineage.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Differentiation - Volume 79, Issues 4–5, April–June 2010, Pages 218–231
نویسندگان
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