کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10801835 | 1055639 | 2016 | 26 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Rapamycin requires AMPK activity and p27 expression for promoting autophagy-dependent Tsc2-null cell survival
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کلمات کلیدی
LKB1Atg13mitogen-activated protein kinase kinase 1/2FDAp27mTORC1LC3DAPINADPHAMPKGFPCDKDMEM4′,6-diamidino-2-phenylindole - 4 '، 6-دیامیدینو-2-فنیلینول5′ AMP-activated protein kinase - 5 'پروتئین کیناز فعال AMPDMSO - DMSODulbecco's modified Eagle's medium - Medal of Eagle اصلاح شده DulbeccoMEK1/2 - MEK1 / 2US Food and Drug Administration - اداره غذا و داروی ایالات متحدهDimethyl sulfoxide - دیمتیل سولفواکسیدmicrotubule-associated protein light chain 3 - زنجیره سبک پروتئینی مرتبط با میکروتوبول 3LAM - لامLymphangioleiomyomatosis - لنفنگیلیمیومیتوزیسnicotinamide adenine dinucleotide phosphate - نیکوتین آمید adenine dinucleotide phosphategreen fluorescent protein - پروتئین فلورسنت سبزliver kinase B1 - کیناز کیناز B1cyclin-dependent kinase - کییناز وابسته به سیکلین
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
پیش نمایش صفحه اول مقاله
![عکس صفحه اول مقاله: Rapamycin requires AMPK activity and p27 expression for promoting autophagy-dependent Tsc2-null cell survival Rapamycin requires AMPK activity and p27 expression for promoting autophagy-dependent Tsc2-null cell survival](/preview/png/10801835.png)
چکیده انگلیسی
Tuberous sclerosis complex (TSC) disease results from inactivation of the TSC1 or TSC2 gene, and is characterized by benign tumors in several organs. Because TSC tumorigenesis correlates with hyperactivation of mTORC1, current therapies focus on mTORC1 inhibition with rapamycin or its analogs. Rapamycin-induced tumor shrinkage has been reported, but tumor recurrence occurs on withdrawal from rapamycin. Autophagy has been associated with development of TSC tumors and with tumor cell survival during rapamycin treatment. mTORC1 and AMPK directly inhibit and activate autophagy, respectively. AMPK is hyperactivated in TSC cells and tumors, and drives cytoplasmic sequestration of the cell-cycle inhibitor p27KIP (p27). Whether AMPK and p27 are involved in rapamycin-induced autophagy and survival of TSC cells remain unexplored. Here, we show that inhibition of AMPK by compound C or by shRNA-mediated depletion of LKB1 reduces activation of autophagy by rapamycin in Tsc2-null cells. Similarly, shRNA-mediated depletion of p27 inhibited rapamycin-induced autophagy. In support of p27 lying downstream of AMPK on the activation of autophagy in Tsc2-null cells, a p27 mutant that preferentially localizes in the cytosol recovered the effect of rapamycin on autophagy in both p27- and LKB1-depleted cells, but a nuclear p27 mutant was inactive. Finally, we show that p27-dependent activation of autophagy is involved in Tsc2-null cell survival under rapamycin treatment. These results indicate that an AMPK/p27 axis is promoting a survival mechanism that could explain in part the relapse of TSC tumors treated with rapamycin, exposing new avenues for designing more efficient treatments for TSC patients.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research - Volume 1863, Issue 6, Part A, June 2016, Pages 1200-1207
Journal: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research - Volume 1863, Issue 6, Part A, June 2016, Pages 1200-1207
نویسندگان
Tania Campos, Javiera Ziehe, Francisco Fuentes-Villalobos, Orlando Riquelme, Daniela Peña, Rodrigo Troncoso, Sergio Lavandero, Violeta Morin, Roxana Pincheira, Ariel F. Castro,