کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10914927 | 1088847 | 2011 | 12 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
N-Myc is a downstream target of RET signaling and is required for transcriptional regulation of p18Ink4c by the transforming mutant RETC634R
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کلمات کلیدی
NPCGNPCDKIMTCMEN2INRN-Mycp18INK4cPTCqPCRCDKInitiator - آغازگرRET - حقTranscription - رونویسیneuronal progenitor cells - سلولهای پیش ساز NeuronalTranscription factor - عامل رونویسیInitiator element - عنصر آغازگرPheochromocytoma - فئوکروموسیتومCDK inhibitor - مهارکننده CDKquantitative polymerase chain reaction - واکنش زنجیره ای پلیمراز کمیCell cycle - چرخه سلولیMedullary thyroid carcinoma - کارسینوم تیروئید مدولریPapillary thyroid carcinoma - کارسینوم پاپیلاری تیروئیدcyclin dependent kinase - کییناز وابسته به کیناز
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
تحقیقات سرطان
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Inherited activating mutations in RET predispose humans to Multiple Endocrine Neoplasia type-2 (MEN2). The MEN2A-specific mutation RETC634R, RET2A, has been shown to simultaneously downregulate the CDKIs p18 and p27, and upregulate cyclin D1. Importantly, the loss of p18 is necessary and sufficient for RET2A-mediated hyperproliferation. The loss of N-Myc in mice results in embryonic lethality due to a lack of neuronal progenitor cells that fail to proliferate, correlate with accumulation of p18 and p27. Therefore, N-Myc may regulate expression of both CDKIs. Also, N-Myc is expressed predominantly in neuroendocrine cells that give rise to the primary cell types affected in MEN2A. Together these studies suggest that N-Myc is a downstream target of RET2A signaling that prevents accumulation of p18 and/or p27. We report that MAPK activation by RET2A leads to a transient induction of N-Myc mRNA and protein levels, and that N-Myc induction is required to maintain low p18 and p27 levels. Induced N-Myc levels correlate with increased binding of N-Myc to an initiator consensus binding site in the p18 promoter, and this binding is essential for RET2A-mediated transcriptional regulation of p18. Finally, loss of N-Myc induction prevents RET2A-mediated hyperproliferation. Our results demonstrate for the first time that N-Myc is a downstream target of RET2A signaling, and propose that induction of N-Myc by RET2A is a key step leading to lower p18 levels during MEN2A tumorigenesis.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Molecular Oncology - Volume 5, Issue 1, February 2011, Pages 24-35
Journal: Molecular Oncology - Volume 5, Issue 1, February 2011, Pages 24-35
نویسندگان
Mandar V. Kulkarni, David S. Franklin,