Ets at 97D: Biological Overview | References
Gene name - Ets at 97D
Cytological map position - 97D7-97D7
Function - transcription factor
Keywords - oogenesis, regulation of mitochondrial mass through regulation of expression of mitochondrial proteins
Symbol - Ets97D
FlyBase ID: FBgn0004510
Genetic map position - 3R:22,736,497..22,738,608 [-]
Cellular location - nuclear
Mitochondria are cellular organelles that perform critical metabolic functions: they generate energy from nutrients but also provide metabolites for de novo synthesis of fatty acids and several amino acids. Thus mitochondrial mass and activity must be coordinated with nutrient availability, yet this remains poorly understood. This study demonstrated that Drosophila larvae grown in low yeast food have strong defects in mitochondrial abundance and respiration activity in the larval fat body. This correlates with reduced expression of genes encoding mitochondrial proteins, particularly genes involved in oxidative phosphorylation. Second, genes involved in glutamine metabolism are also expressed in a nutrient-dependent manner, suggesting a coordination of amino acid synthesis with mitochondrial abundance and activity. Moreover, this study shows that Delg (Ets97D, CG6338, Delg), the Drosophila homologue to the alpha subunit of mammalian transcription factor NRF-2/GABP, is required for proper expression of most genes encoding mitochondrial proteins. The data demonstrate that Delg is critical to adjust mitochondrial abundance in respect to Cyclin D/Cdk4, a growth-promoting complex and glutamine metabolism according to nutrient availability. However, in contrast to nutrients, Delg is not involved in the regulation of mitochondrial activity in the fat body. These findings are the first genetic evidence that the regulation of mitochondrial mass can be uncoupled from mitochondrial activity (Baltzer, 2009).
In eukaryotes, cellular organelles are separated from the cytoplasm through lipid membranes, creating compartments with unique biological properties. Rather than static, organelle size and function are often dynamic, and tightly regulated in response to various stimuli. One of the best-studied organelles are mitochondria, which show large cell-type specific variations in morphology and abundance, demonstrating that mitochondria are highly regulated. Mitochondrial dysfunction is linked to various diseases, including metabolic disorders and cellular aging, therefore these organelles are critical for cellular homeostasis. Mitochondria perform multiple metabolic functions, most notably the generation of energy from carbohydrates, fatty acids and amino acids. Equally important, mitochondria also provide metabolites for anabolic processes such as de novo synthesis of fatty acids and amino acids. Although the metabolic biochemical reactions are well established, how these processes are coordinated in vivo is just beginning to be understood. One interesting question is how nutrients control mitochondrial mass and activity, and how this regulation affects cellular metabolism (Baltzer, 2009).
During cellular growth, amino acids are used for protein synthesis. In higher eukaryotes, essential amino acids are taken up through the diet, whereas nonessential amino acids are synthesized de novo. For the latter, mitochondria are critical, since they provide oxaloacetate for aspartate and asparagine, as well as 2-oxoglutarate (α-ketoglutarate) for glutamate, glutamine, arginine and proline biosynthesis. Of these amino acids, glutamine is particularly interesting: First, many cell types take up large amounts of glutamine, which can be used to produce cytoplasmic NAD+, NAPDH and lactate in a process called glutaminolysis. Second, since the TCA cycle intermediate citrate can be used as a substrate for fatty acid synthesis, glutamine can be converted into 2-oxoglutarate, thus replenishing the TCA cycle. Third, efflux of cytoplasmic glutamine, either taken up or synthesized de novo, is directly linked to the uptake of essential amino acids, both in mammals and Drosophila. Interestingly, all three processes are highly active in cancer cells, under conditions of high metabolic activity. One would therefore expect tight coordination between nutrients, mitochondrial activity and amino acid synthesis, in particular glutamine, yet factors mediating such links have not been described (Baltzer, 2009).
Mitochondria contain their own genome (mtDNA), encoding a small number of proteins required for oxidative phosphorylation (OXPHOS), as well as tRNAs and rRNAs for mitochondrial translation. The majority of mitochondrial proteins are encoded by the nuclear genome, including factors for mitochondrial transcription and translation. These proteins are translated in the cytoplasm and imported into mitochondria. Accordingly, the transcription of these nuclear genes is believed to be rate limiting for mitochondrial mass and activity. To understand the nutrient-specific regulation of mitochondria, one has to characterize how these nuclear transcription factors are regulated in response to nutrients. In Drosophila, genes encoding mitochondrial proteins are highly expressed during the larval growth and feeding period. Subsequently, as the larvae stop feeding at the end of the last larval instar and prepare for metamorphosis, expression of these genes is strongly downregulated (White, 1999; Arbeitman, 2002). Thus Drosophila larval growth is an ideal system to study how mitochondria are regulated in response nutrients in vivo. This has been exploited in recent microarray studies, where expression profiles of normal fed and starved larvae were compared: Indeed, starvation led to a strong downregulation of genes involved in mitochondrial translation, respiration, TCA cycle, fatty acid oxidation and mitochondrial transport (Zinke, 2002: Teleman, 2008). Similar findings have been published using microarrays from fed or starved adult flies (Gershman, 2007). Comparing larval fat body and muscle tissues, Teleman et al. discovered that many of these genes respond in a cell-type specific manner (Teleman, 2008). Therefore, factors must exist that mediate a tissue-specific transcriptional control in response to nutrients. One candidate for such a factor is dFoxo, the fly homologue to mammalian forkhead O-type transcription factors (FoxO family). Importantly, dFoxo does only mediate the nutrient responsiveness for a subset of genes encoding mitochondrial proteins. This implies that other transcription factors must exist, yet they have not been described in Drosophila (Baltzer, 2009).
This study used Drosophila to characterize mitochondria in a developing organism in vivo. Focus was placed on the larval fat body, the fly adipose/liver tissue. Fat body cells are specified during embryogenesis, and show an enormous increase in cell size during larval stages that is accompanied by endoreduplication of mitochondrial DNA to a C-value of ~256. Growth of these cells is directly regulated by nutrient uptake (Baker, 2007), making the larval fat body an ideal system to study mitochondria in response to nutrition and nutrient-sensitive growth-promoting pathways. It was show that low-yeast food conditions, and thus amino acid starvation, leads to strongly reduced mitochondrial abundance and respiration activity. This correlates with reduced expression of genes encoding mitochondrial proteins, including enzymes involved in glutamine metabolism. Moreover, Delg (Ets at 97D), the fly homologue to the alpha subunit of mammalian transcription factor NRF-2/GABP, functions as a key regulator for mitochondrial mass. Surprisingly, reduced mitochondrial mass in delg mutants does not translate into reduced OXPHOS activity. Rather, residual mitochondria compensate by being more active. More importantly, the data show that Delg is critical to adjust mitochondrial abundance and expression levels of enzymes required for glutamine metabolism in response to nutrient availability. Finally, it was observed that the nutrient-sensitive growth-promoting complex Cyclin D/Cdk4 requires Delg for its effect on mitochondria. Thus the data demonstrate how Cyclin D/Cdk4 and Delg coordinate mitochondrial abundance and glutamine metabolism with nutrient availability in vivo (Baltzer, 2009).
As published earlier (The, 1992), Drosophila Delg (Drosophila Ets like gene) is a close homologue to mammalian NRF-2α, being 39% identical in amino acids sequence. In particular, the ETS domain is highly conserved, and 12 of the 13 residues that bind NRF-2α (Batchelor, 1998) are also conserved. Delg was first identified as one of several Drosophila proteins containing an ETS domain (Pribyl, 1991; Chen, 1992; The, 1992). Specific mutants have developmental defects, particularly during oogenesis (Schulz, 1993a; Schulz, 1993b; Gajewski, 1995). A null mutant background (delg613/Df(3R)ro80b) is lethal during pupal stages, whereas a hypomorphic allele (delgtne) gives raise to viable but sterile adults (Schulz, 1993b). To stain for mitochondria, MitoTracker, which gave an abundant staining in the cytoplasm of wild type fat body cells, was first used. In contrast, delg null mutant cells showed a strong decrease in staining. Although reduced, mutant cells still retained staining that localized in a perinuclear manner. When quantified, a 30% reduction in MitoTracker staining was observed in delg mutant cells. Since these stainings were done on fixed tissues, they reflect mitochondrial abundance, but not mitochondrial activity. To further assay mitochondrial mass, NAO was used; this specifically labels the mitochondrial phospholipid cardiolipin, and is commonly used as a good readout to estimate mitochondrial mass. delg mutant cells showed a strong reduction in NAO. Again, residual mitochondria were concentrated around the nucleus. Finally, using electron microscopy, it was noticed that delg mutants had similar numbers of mitochondria, but mitochondria were strongly reduced in size, being on average 50% smaller in area. To test whether this effect is cell-autonomous, delg homozygous mutant clones were induced using the Flp/FRT system. Mutant cells, recognized by the absence of GFP, showed a strong reduction in MitoTracker. Taken together, these data demonstrate that mitochondrial mass is reduced in delg mutant fat body cells in a cell-autonomous manner. In contrast, ectopic expression of Delg did not result in an increase in mitochondrial abundance, demonstrating that Delg is required but not sufficient to control mitochondrial mass in vivo.
In Drosophila as well as other insects, the fat body is the major organ for de novo biosynthesis of fatty acids, leading to the storage of lipids as triacylglycerols. Equally important, the fat body is known to release amino acids, such a glutamine and proline, which are synthesized from the mitochondrial metabolite 2-oxoglutarate. Therefore, one would expect that mitochondrial mass and activity are regulated in response to nutrients in the larval fat body. Indeed, this study shows that strong decreases in mitochondrial abundance, respiration activity as well as expression levels of enzymes involved in glutamine and proline metabolism occur under low-yeast food. Under these feeding conditions, amino acids and fatty acids, which are both provided by yeast, become limited. Delg mutants show very similar phenotypes compared to normal fed controls, and do not show additive phenotypes in respect to mitochondrial abundance and amino acid metabolism upon low-yeast food. It is therefore proposed that Delg functions as a transcription factor to coordinate mitochondrial functions according to nutrient availability. One of these aspects is to adjust the synthesis of non-essential amino acids to the uptake of essential amino acids. In this respect, de novo synthesis of L-glutamine is particularly interesting, as the efflux of its cytoplasmic pool is used, both in mammals and Drosophila, for import of essential amino acids. It is proposed that Delg either directly senses nutrients, most likely amino acids, or is controlled by upstream sensors. Since the nutrient-sensitive Cyclin D/Cdk4 pathway functions through Delg, the latter seems more likely. Given the key role of the fat body in metabolic homeostasis of the whole animal, one might expect that fat body mitochondria be regulated differently from mitochondria in other tissues. Indeed, the phenotypes were specific to the fat body, demonstrating that Delg functions primarily in this tissue to coordinate the different anabolic and catabolic functions of mitochondria (Baltzer, 2009).
Mammalian NRF-2 was identified through its binding to the promoters of cytochrome c oxidase (COX) subunits (Virbasius, 1993; Gugneja, 1995), and has been purified as GABP (LaMarco, 1989). Active NRF-2 is a heterotetramer consisting of two alpha and two beta subunits. The alpha subunits mediate DNA binding, which requires direct GGAA/T repeats in the promoters. Accordingly, electromobility assays as well as luciferase reporter assays have shown that these motifs are functionally important. This is particular well understood for genes encoding electron transport proteins (Carter, 1992; Virbasius, 1993; Villena, 1998; Ongwijitwat, 2004; Ongwijitwat, 2005), as well as for mitochondrial protein import (Blesa, 2004; Blesa, 2006; Blesa, 2007). Furthermore, direct NRF-2 binding to several promoters was shown by chromatin immunoprecipitation (Gleyzer, 2005; Ongwijitwat, 2006). Thus biochemical evidence links NRF-2/GABP to the transcriptional control of nuclear genes encoding mitochondrial proteins. Accordingly, RNAi studies found reduced expression of several COX subunits in cells having reduced NRF-2α levels, leading to reduced COX activity (Ongwijitwat, 2006). Surprisingly, genetic data have not supported the biochemical data: MEFs lacking NRF-2α/GABPα do not have reduced mRNA or protein levels of several putative NRF-2 targets, and mitochondrial phenotypes were not reported (Yang, 2007). Drosophila Delg is the closest fly homologue to mammalian NRF-2α. Two-hybrid data show that Delg can bind to the Drosophila NRF-2β homologue CG32343, and preliminary data show that CG32343 mutants have mitochondrial defects very similar to delg mutants. Taken together, these data show that Delg functions analogues to mammalian NRF-2α, and the data are the first genetic evidence that links any member of the NRF-2α family to mitochondrial biogenesis (Baltzer, 2009).
Of particular interest is the strong reduction in mitochondrial size in the delg mutants. This implies that mitochondrial fusion might be defective, and/or that fission occurs at an increased rate. Indeed, based on microarray data, expression of Opa1-like (CG8479), the fly homologue to mammalian fusion protein OPA1, showed a significant, 2-fold reduction in expression in delg mutant fat body samples. In contrast, fly homologues to mammalian Mitofusins, which are well-established fusion factors (fly homologues Marf/CG3869 and Fuzzy onions/CG4568), were not differently expressed. More work is required to test whether delg mutant have defects in mitochondrial fusion. In addition, when delg homozygous mutant clones were induced, a strong reduction was noted in cell size, yet the nuclear size, shown by the DAPI staining, was not changed, demonstrating growth defects, This is surprising, since endoreplication, and thus nuclear size, normally correlates with cell size in this tissue. Since mitochondrial biogenesis has been shown to correlate with nuclear DNA synthesis, the data suggest that Delg might be involved to link S-phase and potentially cell size to mitochondrial mass. Future work will be required to address this hypothesis (Baltzer, 2009).
Genes involved in mitochondrial OXPHOS activity, including RFeSP and Blw, showed similar reduced expression in the delg mutant or under low yeast nutrition. Importantly, additive defects were detected when delg mutant were grown under low yeast. Moreover, when oxygen consumption was measured in permeabilized fat body tissues, state 3 respirations were strongly affected by low yeast nutrition, yet this was independent of Delg. This demonstrates that factors other than Delg must regulate mitochondrial OXPHOS activity in response to nutrients. One candidate is Spargel/CG9809, the fly homologue to mammalian PGC-1 proteins (Gershman, 2007), which are transcriptional coactivators that control mitochondrial mass and activity in response to external stimuli (Scarpulla, 2008). Indeed, Spargel functions in parallel to Delg, and mediates a link between insulin-signalling and the expression of genes encoding mitochondrial proteins (Tiefenböck, 2010). Therefore, Delg and Spargel mediate two parallel pathways that control mitochondrial mass and OXPHOS activity in response to nutrients (Baltzer, 2009).
Drosophila Cyclin D/Cdk4 is a cyclin-dependent protein kinase complex, and controls cellular growth levels in addition to regulating cell cycle progression. Importantly for this study, overgrowth induced by ectopic expression of Cyclin D/Cdk4 is insensitive to nutrient conditions, demonstrating that the Cyclin D/Cdk4 pathway is nutrient-responsive. This study shows that ectopic expression of Cyclin D/Cdk4 in the larval fat body is sufficient to drive mitochondrial abundance in a Delg-dependent manner, suggesting a mechanism where Cyclin D/Cdk4 coordinate growth levels and mitochondrial mass. Furthermore, one would expect that the transcriptional activity associated with Delg is regulated in response to Cyclin D/Cdk4. Indeed, using lacZ insertions into the loci of several genes encoding mitochondrial proteins, including Blw, clonal expression of Cyclin D/Cdk4 was sufficient to stimulate expression of these genes. However, this effect was restricted to wandering third instar larvae, but was not seen in feeding L1, L2 or L3 larvae. Moreover, when larvae were grown under low-yeast conditions, ectopic expression of Cyclin D/Cdk4 led to reduced expression of these genes, again based on lacZ insertions. It is concluded that Cyclin D/Cdk4 is not a general activator of Delg function, but might mediate a nutrient and/or developmental-dependent control (Baltzer, 2009).
In mammals, D-type cyclins bound to Cdk4 or Cdk6 are best characterized for their functions during cell cycle progression, but several reports have shown additional roles, in particular the regulation of multiple transcription factors by direct binding (Coqueret, 2002). Importantly for this study, mitochondrial size and activity are regulated in response to mammalian Cyclin D1: Knockdown or knockout of Cyclin D1 leads to larger mitochondria that are more active. Conversely, ectopic expression of Cyclin D1 inhibits mitochondrial activity, a function that requires binding to Cdk4. Moreover, Cyclin D1 and NRF-1 are functional linked: Cyclin D1 stimulates NRF-1-dependent transcription, the two proteins interact, and a protein kinase associated to immunoprecipitated vCyclin D1 can phosphorylate NRF-1 (Wang, 2006). This suggests a mechanism where Cyclin D1/Cdk4 inhibit mitochondrial mass and activity through inhibition of NRF-1 function. Thus D-type cyclins bound to Cdk4 have opposite effects on mitochondrial mass in mammals compared to flies, suggesting that different mechanisms have been adopted during evolution to control mitochondria (Baltzer, 2009).
Members of the ets gene family encode transcription factors that regulate the expression of a variety of cellular and viral genes including several protooncogenes. Drosophila was used to elucidate the in vivo function of one family member. Complementation rescue and sequence analysis has shown that the female sterile mutant tiny eggs (tne) is an allele of the Drosophila Ets-related gene Elg (also called D-elg). The mutation of a highly conserved tyrosine residue in the ETS DNA-binding domain of the Elg gene product demonstrates that normal gene function is required for proper follicle ceil migration, chorion formation, and nurse cell chromosome decondensation during Drosophia oogenesis (Schulz, 1993a).
tne is a mutant allele of the Drosophila Elg gene. Normal Elg function is required for proper follicle cell migration, chorion formation, and nurse cell chromosome decondensation. The Tyr-397 --> Cys mutation in the conserved DNA-binding domain suggests that the Elg gene product is functioning as a transcription factor in Drosophila development. The experimental findings on Drosophila Elg and the results of others on the Ets-related genes yan and pnt demonstrate the utility of the Drosophila system in elucidating the functions of c-ets genes in normal cellular processes. Studies on these genes could add significantly to knowledge of ETS proteins as transcriptional regulators in cellular differentiation. Specifically, one could take advantage of the available genetics to position each gene within genetic regulatory regulatory hierarchies that control either egg chamber, photoreceptor, or midline glial cell development; such studies may provide important insights relevant to the elucidation of the functions of ETS proteins in mammalian systems (Schulz, 1993a).
Search PubMed for articles about Drosophila Ets97D
Arbeitman, M. N., et al. (2002). Gene expression during the life cycle of Drosophila melanogaster. Science 297: 2270-2275. PubMed ID: 12351791
Baker, K. D. and Thummel, C. S. (2007). Diabetic larvae and obese flies-emerging studies of metabolism in Drosophila. Cell Metab 6: 257-266. PubMed ID: 17908555
Baltzer, C., Tiefenböck, S. K., Marti, M. and Frei, C. (2009). Nutrition controls mitochondrial biogenesis in the Drosophila adipose tissue through Delg and Cyclin D/Cdk4. PLoS ONE 4(9): e6935. PubMed ID: 19742324
Batchelor, A. H., et al. (1998). The structure of GABPalpha/beta: an ETS domain-ankyrin repeat heterodimer bound to DNA. Science 279: 1037-1041. PubMed ID: 9461436
Blesa, J. R., Hernandez, J. M. and Hernandez-Yago, J. (2004). NRF-2 transcription factor is essential in promoting human Tomm70 gene expression. Mitochondrion 3: 251-259. PubMed ID: 16120358
Blesa, J. R. and Hernandez-Yago, J. (2006). Distinct functional contributions of 2 GABP-NRF-2 recognition sites within the context of the human TOMM70 promoter. Biochem. Cell Biol. 84: 813-822. PubMed ID: 17167546
Blesa, J. R., et al. (2007). NRF-2 transcription factor is required for human TOMM20 gene expression. Gene 391: 198-208. PubMed ID: 17300881
Carter, R. S., Bhat, N. K., Basu, A. and Avadhani, N. G. (1992). The basal promoter elements of murine cytochrome c oxidase subunit IV gene consist of tandemly duplicated ets motifs that bind to GABP-related transcription factors. J. Biol. Chem. 267: 23418-23426. PubMed ID: 1331086
Chen, T., Bunting, M., Karim, F. D. and Thummel, C. S. (1992). Isolation and characterization of five Drosophila genes that encode an ets-related DNA binding domain. Dev. Biol. 151: 176-191. PubMed ID: 1577186
Coqueret, O. (2002). Linking cyclins to transcriptional control. Gene 299: 35-55. PubMed ID: 12459251
Gajewski, K. M. and Schulz, R. A. (1995). Requirement of the ETS domain transcription factor D-ELG for egg chamber patterning and development during Drosophila oogenesis. Oncogene 11: 1033-1040. PubMed ID: 7566961
Gershman, B., et al, (2007). High-resolution dynamics of the transcriptional response to nutrition in Drosophila: a key role for dFOXO. Physiol. Genomics 29: 24-34. PubMed ID: 17090700
Gleyzer, N., Vercauteren, K. and Scarpulla, R. C. (2005). Control of mitochondrial transcription specificity factors (TFB1M and TFB2M) by nuclear respiratory factors (NRF-1 and NRF-2) and PGC-1 family coactivators. Mol. Cell. Biol. 25: 1354-1366. PubMed ID: 15684387
Gugneja, S., Virbasius, J. V. and Scarpulla, R. C. (1995). Four structurally distinct, non-DNA-binding subunits of human nuclear respiratory factor 2 share a conserved transcriptional activation domain. Mol. Cell. Biol. 15: 102-111. PubMed ID: 7799916
LaMarco, K. L. and McKnight, S. L. (1989). Purification of a set of cellular polypeptides that bind to the purine-rich cis-regulatory element of herpes simplex virus immediate early genes. Genes Dev. 3: 1372-1383. PubMed ID: 2558055
Ongwijitwat, S. and Wong-Riley, M. T. (2004). Functional analysis of the rat cytochrome c oxidase subunit 6A1 promoter in primary neurons. Gene 337: 163-171. PubMed ID: 15276212
Ongwijitwat, S. and Wong-Riley, M. T. (2005). Is nuclear respiratory factor 2 a master transcriptional coordinator for all ten nuclear-encoded cytochrome c oxidase subunits in neurons? Gene 360: 65-77. PubMed ID: 16126350
Ongwijitwat, S., Liang, H. L., Graboyes, E. M. and Wong-Riley, M. T. (2006). Nuclear respiratory factor 2 senses changing cellular energy demands and its silencing down-regulates cytochrome oxidase and other target gene mRNAs. Gene 374: 39-49. PubMed ID: 16516409
Pribyl, L. J., Watson, D. K., Schulz, R. A. and Papas, T. S. (1991). D-elg, a member of the Drosophila ets gene family: sequence, expression and evolutionary comparison. Oncogene 6: 1175-1183. PubMed ID: 1713660
Scarpulla, R. C. (2008). Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol. Rev. 88: 611-638. PubMed ID: 18391175
Schulz, R. A., The, S. M., Hogue, D. A., Galewsky, S. and Guo, Q. (1993a). Ets oncogene-related gene Elg functions in Drosophila oogenesis. Proc. Natl. Acad. Sci. 90: 10076-10080. PubMed ID: 8234259
Schulz, R. A., Hogue, D. A. and The, S. M. (1993b). Characterization of lethal alleles of D-elg, an ets proto-oncogene related gene with multiple functions in Drosophila development. Oncogene 8: 3369-3374. PubMed ID: 8247539
Teleman, A. A., Hietakangas, V., Sayadian, A. C. and Cohen, S. M. (2008). Nutritional control of protein biosynthetic capacity by insulin via Myc in Drosophila. Cell. Metab. 7: 21-32. PubMed ID: 18177722
The, S. M., et al. (1992). Molecular characterization and structural organization of D-elg, an ets proto-oncogene-related gene of Drosophila. Oncogene 7: 2471-2478. PubMed ID: 1461651
Tiefenböck, S. K., Baltzer, C., Egli, N. A. and Frei, C. (2010). The Drosophila PGC-1 homologue Spargel coordinates mitochondrial activity to insulin signalling. EMBO J. 29(1): 171-83. PubMed ID: 19910925
Villena, J. A., et al. (1998), Regulation of mitochondrial biogenesis in brown adipose tissue: nuclear respiratory factor-2/GA-binding protein is responsible for the transcriptional regulation of the gene for the mitochondrial ATP synthase beta subunit. Biochem J. 331: 121-127. PubMed ID: 9512469
Virbasius, J. V., Virbasius, C. A. and Scarpulla, R. C. (1993). Identity of GABP with NRF-2, a multisubunit activator of cytochrome oxidase expression, reveals a cellular role for an ETS domain activator of viral promoters. Genes Dev. 7: 380-392. PubMed ID: 8383622
Wang, C., et al. (2006). Cyclin D1 repression of nuclear respiratory factor 1 integrates nuclear DNA synthesis and mitochondrial function. Proc. Natl, Acad, Sci. 103: 11567-11572. PubMed ID: 16864783
White, K. P., Rifkin, S. A., Hurban, P. and Hogness, D. S. (1999). Microarray analysis of Drosophila development during metamorphosis. Science 286: 2179-2184. PubMed ID: 10591654
Yang, Z. F., Mott, S. and Rosmarin, A. G. (2007). The Ets transcription factor GABP is required for cell-cycle progression. Nat. Cell Biol. 9: 339-346. PubMed ID: 17277770
Zinke, I., et al. (2002). Nutrient control of gene expression in Drosophila: microarray analysis of starvation and sugar-dependent response. EMBO J. 21: 6162-6173. PubMed ID: 12426388
date revised: 10 July 2010
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