A dual program for translation regulation in cellular proliferation and differentiation.

A dichotomous choice for metazoan cells is between proliferation and differentiation. Measuring tRNA pools in various cell types, we found two distinct subsets, one that is induced in proliferating cells, and repressed otherwise, and another with the opposite signature. Correspondingly, we found that genes serving cell-autonomous functions and genes involved in multicellularity obey distinct codon usage. Proliferation-induced and differentiation-induced tRNAs often carry anticodons that correspond to the codons enriched among the cell-autonomous and the multicellularity genes, respectively. Because mRNAs of cell-autonomous genes are induced in proliferation and cancer in particular, the concomitant induction of their codon-enriched tRNAs suggests coordination between transcription and translation. Histone modifications indeed change similarly in the vicinity of cell-autonomous genes and their corresponding tRNAs, and in multicellularity genes and their tRNAs, suggesting the existence of transcriptional programs coordinating tRNA supply and demand. Hence, we describe the existence of two distinct translation programs that operate during proliferation and differentiation.

Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells.

MicroRNAs are emerging as important regulators of cancer-related processes. The miR-21 microRNA is overexpressed in a wide variety of cancers and has been causally linked to cellular proliferation, apoptosis, and migration. Inhibition of mir-21 in MCF-7 breast cancer cells causes reduced cell growth. Using array expression analysis of MCF-7 cells depleted of miR-21, we have identified mRNA targets of mir-21 and have shown a link between miR-21 and the p53 tumor suppressor protein. We furthermore found that the tumor suppressor protein Programmed Cell Death 4 (PDCD4) is regulated by miR-21 and demonstrated that PDCD4 is a functionally important target for miR-21 in breast cancer cells.

Characterization and location of secretory phospholipase A2 groups IIE, V, and X in the rat brain.

Secretory phospholipases A(2) (sPLA(2)) form a diverse family of enzymes involved in a variety of physiologic and pathologic processes. Common among all sPLA(2) is the ability to cleave the second position of phospholipids, thereby releasing fatty acid and a lysophospholipid. Several sPLA(2) have been cloned and characterized in various tissues and receptors have been identified. In the nervous system, sPLA(2) groups IB, IIA, IIE, IIF, V, and XII have been identified, and binding sites for sPLA(2) have been found. Here, we report sPLA(2)-IIE and sPLA(2)-X in rat brain as well as in neurons in primary culture. We furthermore confirm the presence of sPLA(2)-V in rat brain and demonstrate the presence of sPLA(2)-V in primary neuronal cultures. The distribution of sPLA(2)-IIE, V, and -X seems to be mainly neuronal, with the highest abundance occurring in the cerebral cortex and hippocampus. We also find that sPLA(2)-IIE, -V, and -X are differentially induced by kainic acid. This study supports the concept that sPLA(2) heterogeneity in brain is functionally relevant and responsive to seizures.

Expression and induction of secretory phospholipase A2 group IB in brain.

Secretory phospholipases A2 (sPLA2) form a diverse family of enzymes involved in physiologic and pathologic processes. Common among all sPLA2 is the ability to cleave acyl groups of phospholipids at C2 of the glycerol backbone, thereby releasing fatty acid and a lysophospholipid. Several sPLA2 have been cloned and characterized in various tissues. Furthermore, receptors have been identified. In the nervous system sPLA2 groups IIA, IIE, IIF, V, and XII have been identified, and binding sites for sPLA2 group IB (sPLA2-IB) have been found. Here, we report sPLA2-IB in rat and human brain as well as in neurons in primary culture. The distribution of sPLA2-IB seems to be mainly neuronal, with the highest abundance occurring in the cerebral cortex and hippocampus. We also find that genes encoding sPLA2-IB are induced by kainic acid and by electroshock-induced convulsions. Based on the present results we suggest that sPLA2-IB may be a neuronal intercellular signalling modulator.

Expression and location of mRNAs encoding multiple forms of secretory phospholipase A2 in the rat retina.

Low-molecular-weight secretory phospholipases A(2) (sPLA(2)s) are a subgroup of PLA(2)s, which are secreted, bind to receptors, and may act as intercellular signaling modulators. At least 10 different groups have been characterized in mammals, and there is expanding evidence of the significance of sPLA(2)s in neuronal signaling and survival [Kolko et al. (1996) J. Biol. Chem. 271: 32722-32728]. To date, no retinal sPLA(2)s have been cloned or characterized. We evaluated the existence and abundance of sPLA(2) subtypes in rat retina and explored their possible involvement in light-induced retinal damage. We designed primers to identify the sPLA(2)s in rat retina, based on known sequences of sPLA(2)-specific mRNAs in other tissues. RNA was isolated from rat retina, and cDNA was produced and used for PCR cloning to identify the novel subtypes of sPLA(2). Our study revealed the presence of mRNAs encoding sPLA(2)-IB, -X, -V, -IIE, -IIA, and -IIF in the retina, and quantification by real-time PCR revealed different abundances of the sPLA(2)s. We showed a time-dependent gene induction of sPLA(2)-X, -IB, and -V in light-induced retinal damage. We further explored the location of sPLA(2)-IB by in situ hybridization and immunohistochemistry. This study is the first to reveal the presence, abundance, and induction of mRNAs encoding sPLA(2)s in rat retina. We suggest that these enzymes are themselves intercellular signaling modulators of retinal cell function and perhaps also of retinal degeneration.