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在人包皮成纤维细胞中敲低MBP-1会诱导p53-p21依赖性衰老。

Knockdown of MBP-1 in human foreskin fibroblasts induces p53-p21 dependent senescence.

作者信息

Ghosh Asish K, Kanda Tatsuo, Steele Robert, Ray Ratna B

机构信息

Department of Pathology, Saint Louis University, St. Louis, Missouri, United States of America.

出版信息

PLoS One. 2008;3(10):e3384. doi: 10.1371/journal.pone.0003384. Epub 2008 Oct 13.

DOI:10.1371/journal.pone.0003384
PMID:18852884
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2557062/
Abstract

MBP-1 acts as a general transcriptional repressor. Overexpression of MBP-1 induces cell death in a number of cancer cells and regresses tumor growth. However, the function of endogenous MBP-1 in normal cell growth regulation remains unknown. To unravel the role of endogenous MBP-1, we knocked down MBP-1 expression in primary human foreskin fibroblasts (HFF) by RNA interference. Knockdown of MBP-1 in HFF (HFF-MBPsi-4) resulted in an induction of premature senescence, displayed flattened cell morphology, and increased senescence-associated beta-galactosidase activity. FACS analysis of HFF-MBPsi-4 revealed accumulation of a high number of cells in the G1-phase. A significant upregulation of cyclin D1 and reduction of cyclin A was detected in HFF-MBPsi-4 as compared to control HFF. Senescent fibroblasts exhibited enhanced expression of phosphorylated and acetylated p53, and cyclin-dependent kinase inhibitor, p21. Further analysis suggested that promyolocytic leukemia protein (PML) bodies are dramatically increased in HFF-MBPsi-4. Together, these results demonstrated that knockdown of endogenous MBP-1 is involved in cellular senescence of HFF through p53-p21 pathway.

摘要

髓鞘碱性蛋白-1（MBP-1）作为一种通用转录抑制因子发挥作用。MBP-1的过表达在多种癌细胞中诱导细胞死亡并使肿瘤生长消退。然而，内源性MBP-1在正常细胞生长调节中的功能仍不清楚。为了阐明内源性MBP-1的作用，我们通过RNA干扰敲低了原代人包皮成纤维细胞（HFF）中MBP-1的表达。在HFF（HFF-MBPsi-4）中敲低MBP-1导致过早衰老的诱导，表现为扁平的细胞形态，并增加了衰老相关的β-半乳糖苷酶活性。对HFF-MBPsi-4的流式细胞术分析显示大量细胞在G1期积累。与对照HFF相比，在HFF-MBPsi-4中检测到细胞周期蛋白D1显著上调和细胞周期蛋白A减少。衰老的成纤维细胞表现出磷酸化和乙酰化p53以及细胞周期蛋白依赖性激酶抑制剂p21的表达增强。进一步分析表明，早幼粒细胞白血病蛋白（PML）小体在HFF-MBPsi-4中显著增加。总之，这些结果表明敲低内源性MBP-1通过p53-p21途径参与HFF的细胞衰老。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ab1/2557062/70cc5966c87f/pone.0003384.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ab1/2557062/78e634962f12/pone.0003384.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ab1/2557062/b470c4ad4df5/pone.0003384.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ab1/2557062/750418a60d79/pone.0003384.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ab1/2557062/f2cd4e0fe0d3/pone.0003384.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ab1/2557062/70cc5966c87f/pone.0003384.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ab1/2557062/78e634962f12/pone.0003384.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ab1/2557062/b470c4ad4df5/pone.0003384.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ab1/2557062/750418a60d79/pone.0003384.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ab1/2557062/f2cd4e0fe0d3/pone.0003384.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ab1/2557062/70cc5966c87f/pone.0003384.g005.jpg

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