miR-34转录因子的相互调控

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MicroRNAs (miRNAs) are small non-coding RNAs that regu-late gene expression. Several studies have linked dysregulation of miRNA with tumorigenesis. The TP53 is one of the most commonly mutated genes in human cancers, and its gene product p53 activates transcription of a set of miRNA including the miR-34 family of miRNA. The miR-34 family regulates cell cycle progres-sion, cellular senescence and apoptosis, but the targets of miR-34 are not completely defined. We recently found that miR-34a inhibits SIRT1, a gene that regulates cellular senescence and limits longevity. SIRT1 also regulates p53 dependent apoptosis through deacetylating and stabilizing p53. We also discovered that SIRT1 mediates miR-34a activation of apoptosis by regulating p53 activity. Based on this observation, we propose a positive feedback loop, in which p53 induces expression of miR-34a which suppresses SIRT1, increasing p53 activity.

Introduction

MicroRNAs (miRNAs) were first identified as regulators of development in C. elegans .1,2 Subsequent studies showed that these small non-coding miRNA inhibit target protein expression by post-transcriptional repression.3,4 There are two major challenges to the study of miRNA networks. First, each miRNA has hundreds of putative target genes. Mammalian miRNA target recognition occurs through the regions of specific sequence complementarity between the first 6–8 nucleotides of each miRNA, called the “seed region,” and the 3'UTR regions of mRNA targets.5,6 Therefore an individual miRNA has the potential to regulate many different genes. Second, many genes have multiple putative miRNA binding sites in their 3' untranslated region (3'UTR). Since miRNAs can regulate a target gene cooperatively or antagonistically, the effects of each individual miRNA are hard to define. Adding to the complexity, recent articles demonstrate that the coding regions of genes can be the target of miRNAs.7-9 New bioinformatic techniques are needed to increase the biological sensitivity, specificity and accuracy of in silico analysis of miRNA targets.

TP53 is tumor suppressor gene which is activated by DNA damage such as radiation, oxidative stress and chemotherapeutic drug.10,11 Many cancers have mutations in the p53 pathway.12,13 Normally p53 is destabilized and degraded, so resting cells contain small amounts of p53. However, genotoxic stress leads to stabilization of p53 which then accumulates inside cells, inducing cell cycle arrest, senescence and apoptosis.14 p53 regulates cell proliferation in part by acting as a transcription factor, inducing expression of many genes.15

Several groups independently discovered that p53 regulates the expression of the miRNA family miR-34 that includes miR-34a, miR-34b and miR-34c. The miR-34 family modulates cell cycle progression, senescence and apoptosis.16-22 In this Perspective, we emphasize two novel roles of miR-34a. First we propose that miR-34a plays a pivotal role in a positive feedback loop that includes p53, miR-34a and SIRT1. Second we discuss the possibility that miR-34a regulates senescence and metabolism.

Cancer and miRNAs

MiRNAs play an important role in the development, physiology and pathophysiology of animals and plants. Recent studies show that miRNAs are expressed in unique patterns in tumors, and are involved in tumorigenesis, progression and metastasis. For example, the B-cell integration cluster (BIC) gene encodes miR-155.23 An increase in miR-155 levels is detected in lymphomas, lung cancer, breast cancer and pancreatic cancers.24 The miR-15a and miR-16-1 cluster on chromosome13q14 is frequently deleted in patients of chronic lymphocytic leukemia (CLL).25 BCL2 in one of the targets of this cluster.26 In prostate cancer, this miR-15a/16-1 cluster acts as tumor suppressor genes by inhibiting CCND1 and WNT3A.27 Overexpression of let-7 inhibits lung cancer cell proliferation by suppressing expression of RAS or HMGA2.28,29 MiR-21 induces tumorigenesis in MCF-7 breast cancer cells and RKO colorectal cancer cells.30,31 Mir-221/222 can regulate cell cycle progression by inhibiting p27 (Kip1) protein expression in several cancer.32,33 Metastatic breast cancers have reduced expression of miR-335, miR-126 and miR-206, suggesting that the loss of specific miRNAs facilitates metastasis.34 Thus abnormal miRNA expression can accelerate tumor growth through the dysregulation of target onco-genes.35-38

*Correspondence to: Munekazu Yamakuchi; 958 Ross Bldg.; 720 Rutland Ave.; The Johns Hopkins University School of Medicine; Baltimore, Maryland 21205 USA; Tel.: 410.614.0071; Fax: 410.955.0485; Email: myamaku1@ Submitted: 01/02/09; Accepted: 01/02/09

Previously published online as a Cell Cycle E-publication: /journals/cc/article/7753Perspective

MiR-34, SIRT1 and p53

The feedback loop

Munekazu Yamakuchi 1,* and Charles J. Lowenstein 1,2

Departments of 1Medicine and 2Pathology; The Johns Hopkins University School of Medicine; Baltimore, Maryland, USA

Key words: microRNA (miRNA), p53, miR-34, apoptosis, SIRT1

[Cell Cycle 8:5, 712-715; 1 March 2009]; ©2009 Landes Bioscience