MicroRNAs and the regulation of cell death

doi:10.1016/j.tig.2004.09.010

Trends in Genetics

Volume 20, Issue 12, December 2004, Pages 617-624

https://doi.org/10.1016/j.tig.2004.09.010 Get rights and content

Programmed cell death, or apoptosis, is ubiquitous, both during development and in the adult. Many components of the evolutionarily conserved machinery that brings about and regulates cell death have been identified, and all of these are proteins. However, in the past three years it has become clear that roughly 1% of predicted genes in animals encode small noncoding RNAs known as microRNAs, which regulate gene function. Here we review the recent identification of microRNA cell death regulators in Drosophila, hints that such regulators are also likely to exist in mammals, and more generally the approaches and tools that are now available to probe roles for noncoding RNAs in the control of cell death.

Section snippets

miRNAs, their abundance and mechanisms of action

The first miRNAs to be discovered, lin-4 and let-7, were identified genetically, based on their roles in the development of Caenorhabditis elegans (reviewed in Ref. [9]). More recently it has become clear that lin-4 and let-7 are the founding members of a large class of small regulatory RNAs. Multiple groups, using direct cloning of small RNAs, biochemical purification of ribonucleoprotein (RNP) particles, and computational approaches that involve searches for evolutionarily conserved stem-loop

The Drosophila cell death machine

The core of the cell death machine in animals consists of members of a family of proteases known as caspases (reviewed in Ref. [13]). Caspases become activated in response to many different death signals. Active caspases then cleave several different cellular substrates, ultimately leading to cell death and corpse phagocytosis. Most if not all cells constitutively express caspase zymogens (inactive precursors) sufficient to bring about apoptosis Thus, the key to cell death and survival

Identifying miRNA targets and new miRNA regulators of cell death: the computational approach

The above observations with mir-14 and bantam highlight the fact that to understand how miRNAs function to regulate cell death, proliferation, fat storage or any other process we must identify their mRNA targets. In plants this has proven to be reasonably straightforward because plant miRNAs typically show high levels of complementarity with their target transcripts, thus facilitating target identification through more standard homology searches [24]. By contrast, miRNAs in animals are in

Inactivating miRNAs

To determine the normal functions of specific miRNAs we need to be able to characterize their loss-of-function phenotypes (Figure 4). However, classical genetic mutations are available for less than a handful of miRNAs, and this situation is unlikely to change soon. Fortunately, it has recently been discovered that 2′-O-methyl oligoribonucleotides can be used to knock down, if not out, the activity of specific miRNAs. Briefly, when 2′-O-methyl oligoribonucleotides are introduced into cells in

miRNA regulators of cell death in mammals?

miRNA regulators of cell death in C. elegans and mammals have not yet been identified. This might seem surprising, particularly in the case of C. elegans, because it was genetic screens in this organism that first demonstrated that cell death was under genetic control, and in which several key components of the evolutionarily conserved cell death machine, namely Ced-4 (Apaf-1) and Ced-3 (caspases), were first described (reviewed in Ref. [35]). There are several probable explanations for this

Cell death and miRNAs: the way forward

Multiple miRNAs that function as cell death inhibitors, mir-14, bantam, and probably members of the mir-2 and/or mir-13 family, have been identified in Drosophila. In addition, we identified three other death-suppressing miRNAs in our GMREP-based overexpression screen (P. Xu and B. Hay, unpublished). This screen of 8000 insertions is far from saturating because the Drosophila genome contains roughly 12 000 genes [50] and P elements show clear insertion-site specificity [51]. Therefore, it is

Acknowledgements

The authors' work described in this article was supported by The Ellison Medical Foundation, The Margaret E. Early Medical Trust, NIH grants GM070956 and GM57422 (B.A.H.) and a Gosney Fellowship (P.X.). We apologize to authors whose work could not be cited directly due to space limitations.

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^*: Current address: Department of Physiology, Howard Hughes Medical Institute, UC San Francisco, Genetics, Development and Behavioral Sciences Building, 1550 4^th St, San Francisco, CA 94143-0725, USA.

View full text

Trends in Genetics

MicroRNAs and the regulation of cell death

Section snippets

miRNAs, their abundance and mechanisms of action

The Drosophila cell death machine

Identifying miRNA targets and new miRNA regulators of cell death: the computational approach

Inactivating miRNAs

miRNA regulators of cell death in mammals?

Cell death and miRNAs: the way forward

Acknowledgements

Curr. Opin. Immunol.

Cell

Curr. Biol.

Curr. Opin. Cell Biol.

Curr. Biol.

Cell

Cell

Curr. Opin. Genet. Dev.

Cell

Cell

Cell

Curr. Biol.

Cancer Cell

Mol. Cell

Cell

Dev. Biol.

Trends Genet.

Semin. Cancer Biol.

J. Biol. Chem.

Cell

Mol. Cell

J. Biol. Chem.

J. Biol. Chem.

Getting back on track, or what to do when apoptosis is de-railed: recoupling oncogenes to the apoptotic machinery

Cancer Biol. Ther.

Apoptosis in neurodegenerative disorders

Nature Reviews Mol. Cell Biol.

A decade of caspases

Oncogene

Understanding IAP function and regulation: a view from Drosophila

Cell Death Differ.

P element insertion-dependent gene activation in the Drosophila eye

Proc. Natl. Acad. Sci. U. S. A.

Identification of novel genes coding for small expressed RNAs

Science

Lipotoxic diseases

Annu. Rev. Med.