Cancer Research CTRC-AACR San Antonio Breast Cancer Symposium AACR Conference on Molecular Diagnostics - 2008
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Guo, Q. M.
Right arrow Articles by Liu, E. T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Guo, Q. M.
Right arrow Articles by Liu, E. T.
[Cancer Research 60, 5922-5928, November 1, 2000]
© 2000 American Association for Cancer Research

Advances in Brief

Identification of c-Myc Responsive Genes Using Rat cDNA Microarray

Qingbin M. Guo, Renae L. Malek, Sunkyu Kim, Chia Chiao, Mei He, Mauro Ruffy, Krishna Sanka, Norman H. Lee, Chi V. Dang and Edison T. Liu1

Molecular Signaling and Oncogenesis Section, Department of Cancer and Cell Biology, Medicine Branch, Division of Clinical Science, National Cancer Institute, Bethesda, Maryland 20892 [Q. M. G., C. C., M. H., M. R., K. S., E. T. L.]; Department of Molecular and Cellular Biology, The Institute for Genomic Research, Rockville, Maryland 20850 [R. L. M., N. H. L.]; and Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 [S. K., C. V. D.]


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 
c-Myc functions through direct activation or repression of transcription. Using cDNA microarray analysis, we have identified c-Myc-responsive genes by comparing gene expression profiles between c-myc null and c-myc wild-type rat fibroblast cells and between c-myc null and c-myc null cells reconstituted with c-myc. From a panel of 4400 cDNA elements, we found 198 genes responsive to c-myc when comparing wild-type or reconstituted cells with the null cells. The plurality of the named c-Myc-responsive genes that were up-regulated, including 30 ribosomal protein genes, are involved in macromolecular synthesis and metabolism, suggesting a major role of c-Myc in the regulation of protein synthetic and metabolic pathways. When ectopically overexpressed, c-Myc induced a different and smaller set of c-Myc-responsive genes as compared with the physiologically expressed c-Myc condition. Thus, these results from expression profiling suggest a new primary function for c-Myc and raise the possibility that the physiological and transforming functions of c-myc may be separable.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results and Discussion
 REFERENCES
 
The proto-oncogene c-myc plays an important role in the control of cell proliferation, differentiation, and apoptosis, and its aberrant expression is a commonly found molecular defect in human cancers (1) . c-Myc functions through the transcriptional activation or repression of its target genes. Using a variety of methods, such as subtractive hybridization, representational difference analysis, and differential display in systems with enforced c-Myc overexpression, only a small number of c-Myc target genes have been identified, although none has been shown to mediate a physiological function of Myc (2) . Recently, the authenticity of some c-Myc target genes was re-evaluated in light of experiments in Rat1 fibroblasts bearing homozygous deletion of c-myc (3) . The c-myc null rat fibroblasts continue to grow and show no detectable expression of N-myc or L-myc, which may compensate for the deficiency of c-myc (4) . Using this system, Bush et al. (3) demonstrated that 9 of 11 previously reported c-Myc target genes appeared not differentially expressed between c-myc wild-type and c-myc null cells, suggesting that physiological expression of c-Myc may potentially regulate a different set of genes than overexpressed c-Myc. Given the limitations of the technologies used previously, we used cDNA microarray analyses to look for genes that are differentially expressed between c-myc wild-type and c-myc null cells. The advantage of this approach is the comprehensive nature of the technology and the ability to interrogate multiple cellular conditions so as to "triangulate" the true set of c-Myc-responsive genes. In this study, we report the identification of 245 genes that are responsive to the physiologically expressed or overexpressed c-Myc. Most of these c-Myc-responsive genes are involved in macromolecular synthesis and metabolism. Our findings are consistent with recent genetic studies of Drosophila c-myc (5) , suggesting that c-Myc is an important regulator of protein synthetic and metabolic pathways.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results and Discussion
 REFERENCES
 
EST2 Clones and Cell Lines.
Our rat microarray contained 4400 EST cDNAs clones selected from the Rat Gene Index of the Institute for Genomic Research. A small set of redundant clones (5%) were included for quality control. Selected clones were from 52,000 3' ESTs generated from 12 different libraries constructed from 10 distinct tissues and two PC12 cell lines. All clones are available through the American Type Culture Collection. The clones used for our microarray were sequence-verified by generating both 5' and 3' ESTs. The EST sequences have been deposited into the GenBank database dbEST.3

The somatic c-myc null cells (Ho15.19) and its parental c-myc wild-type Rat1 cells (TGR-1) were from John Sedivy (Brown University, Providence, RI) and cultured as described (4) . The log-phase cells were harvested at 60% confluence. For serum starvation condition, the cells were grown to confluence and then cultured without serum for 48 h. The cell lines overexpressing c-Myc were generated by cotransfection of pBabe-puro vector and CM19, which contains genomic c-myc gene under the control of a long terminal repeat promoter, into Ho15.19 or TGR-1 cells.

cDNA Microarray and Data Analysis.
We fabricated our rat cDNA microarrays essentially as described previously (6) . The plasmids of EST clones were purified using the QiaPrep Turbo kit (Qiagen). The cDNA inserts were amplified by PCR for 30 cycles with M13 froward and reverse primers. The PCR products were verified by gel electrophoresis, purified, and arrayed robotically onto polylysine-coated glass microscope slides with a GeneMachine arrayer (San Carlos, CA). The microarrays were then postprocessed to denature and immobilize the DNA (6) .

The cDNA probes were made from total RNAs with cy5- or cy3-dUTP (Amersham Pharmacia) and Superscript II polymerase (Life Technologies, Inc.) as described (6) . Microarrays were hybridized with probes, washed, and then scanned using an Axon scanner (Foster City, CA), with the sample intensities for cy5 and cy3 collected separately. The normalization of the sample intensities and calculation of the calibrated fluorescence ratios after background subtraction were as described (7 , 8) .

Northern Hybridization.
The cDNA probes were made by random primer labeling. Fifteen µg of total RNA were separated on a formaldehyde 1.2% agarose gel, transferred to a Hybond-N nylon membrane (Amersham), and then immobilized by UV irradiation. The hybridization was carried out using ExpressHyb solution (Clontech), and bands were quantitated using a PhosphorImager (Molecular Dynamics).


   Results and Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
REFERENCES
 
Some Genes Are Differentially Expressed between c-myc Wild-Type and c-myc Null Cells.
Because c-Myc is actively expressed in growing cells, we first compared gene expression profiles between c-myc null cells (Null) and its parental c-myc wild-type cells (WT) during log-phase growth, as diagrammed in Fig. 1Citation . Using the criteria of at least 2-fold difference in expression in two separate experiments, we found 319 reproducible gene expression differences, representing 283 distinct genes, between WT cells and Null cells during log-phase growth. One hundred eighty-eight of these genes were up-regulated, and 95 were down-regulated by 2.3–15-fold in WT cells. That 7.3% (319 of 4400) of the gene elements on the microarray were differentially regulated is highly significant, because the false-positive rate of our system is only 0.2% (8 of 4400) at an expression threshold of 2-fold difference.



View larger version (21K):
[in this window]
[in a new window]
  		Fig. 1. Experimental scheme and summary of results. Some of the known genes were represented by more than one EST clone.

 
Ectopically Expressed c-Myc Can Recover the Gene Expression Profiles in the c-myc Null Cells.
To validate that the differential gene expression we found truly depends on the expression of c-Myc, we ectopically expressed c-Myc in the c-myc null cells (Null+MYC) and compared the gene expression between Null+MYC cells and Null cells (Fig. 1)Citation . We found that these c-myc-reconstituted cells behaved like their wild-type counterparts. As shown in Fig. 2Citation , the gene expression profile of Null+MYC cells resembled that of the WT cells, because they shared 198 differentially expressed genes (represented by 227 EST clones on the microarray) when each was compared with Null cells at log phase (Figs. 1Citation and 2Citation , A and B). The correlation between the Null+MYC/Null comparison and the WT/Null comparison (r = 0.854) is very similar to that between two repeated WT/Null comparisons (r = 0.846; Fig. 2, C and DCitation ). By comparing log-phase Null+MYC cells and Null cells, we were also able to eliminate those gene expression differences attributable to potential clonal variations between log-phase WT and Null cells. Therefore, these 198 overlapping genes, which were differentially expressed between log-phase WT and Null cells, and also between Null+MYC and Null cells, represent a stringent list of c-Myc-responsive genes in log-phase growth. Although all genes listed are responsive to the presence of c-Myc, we acknowledge that only some of these genes will be direct targets of c-Myc, and others will be indirect targets regulated by other c-Myc-responsive gene products. Our current experimental approach cannot distinguish between the two mechanisms of induction but identifies the universe of RNAs whose levels are correlated with the expression of c-Myc.



View larger version (36K):
[in this window]
[in a new window]
  		Fig. 2. Comparisons between WT and Null cells or between Null+MYC and Null cells during log-phase growth. A, comparison of WT and Null cells at log phase. A section of the microarray is shown. Total RNA from WT cells was labeled with cy5-dUTP; total RNA from Null cells was labeled with cy3-dUTP. B, comparison of Null+MYC and Null cells at log phase. The same section of the microarray as in A is shown. Total RNA from Null+MYC cells was labeled with cy5-dUTP; total RNA from Null cells was labeled with cy3-dUTP. C, scatter plot of the calibrated ratios (log scale) in the two independent comparisons between WT cells and Null cells. D, scatter plot of the calibrated ratios (log scale) in the comparisons between WT cells and Null cells (vertical axis) and between Null+MYC cells and Null cells (horizontal axis).

 
Of these 198 c-Myc-responsive genes, 124 genes were up-regulated by c-Myc, which represent 96 known genes and 28 unnamed ESTs. There were 74 genes down-regulated by c-Myc, representing 46 known genes and 28 unknown genes. The known genes are listed in Tables 1Citation and 2Citation .4 Among the c-Myc-responsive genes we observed, cyclin D1, Cdc2, LDH-A, and MHC-I{alpha} have been reported previously as c-Myc targets (2) . Cyclin D1 has been reported to be either up-regulated or down-regulated by c-Myc in different studies (9 , 10) . In our cDNA microarray study, cyclin D1 was consistently down-regulated by c-Myc in WT cells compared with Null cells, and this was confirmed by Northern hybridization (Fig. 3)Citation . The Myc-mediated decrease of cyclin D1 expression was also observed when Null cells were compared with Null+MYC cells or WT cells were compared with wild-type cells overexpressing c-Myc (WT+MYC; Fig. 3Citation ). Although it has been reported that the expression of LDH-A is not changed between c-myc wild-type cells and c-myc null cells (3) , we found that LDH-A is consistently induced in WT cells or Null+MYC cells when they were compared with Null cells in our microarray analysis. This result was also confirmed by Northern hybridizations (Fig. 3)Citation . In addition to cyclin D1 and LDH-A, we chose 10 other genes from Tables 1Citation and 2Citation and examined their expressions by Northern hybridizations in Null, Null+MYC, WT, and WT+MYC cells. Except for the two genes whose expression was not detectable by Northern, all others were differentially expressed, in concordance with our microarray results (Fig. 3)Citation . In a limited number of instances, reported c-Myc target genes did not appear to be differentially expressed between WT and Null cells in our microarray analysis (e.g., RCC1, ODC, and Cad). Several factors might explain these discrepancies:


View this table:
[in this window]
[in a new window]
  		Table 1 Genes up-regulated by c-Myca

 

View this table:
[in this window]
[in a new window]
  		Table 2 Genes down-regulated by c-Myca

 


View larger version (55K):
[in this window]
[in a new window]
  		Fig. 3. Confirmation of differentially expressed genes in microarray analysis by Northern hybridizations. (-/-), Null cells; (+/+), WT cells; (-/-)+Myc, Null+MYC cells; (+/+)+Myc, WT+MYC cells. The cDNA probes were: i, c-myc; ii, CPD (carboxypeptidase D); iii, Cyclin D1; iv, GCN1; v, PGAM (peptidylglycine {alpha}-amidating monooxygenase); vi, rp-S12 (ribosomal protein S12); vii, rp-L6 (ribosomal protein L6); viii, NPM (nucleophosmin or nucleolar phosphoprotein B23); ix, {alpha}-NAC (nascent polypeptide associated complex); x, LDH-A; xi, 28S rRNA (inverted picture of agarose gel stained with ethidium bromide solution); xii, actin.

 
(a) The criteria we set forth for defining c-Myc-responsive genes were very stringent. A greater than 2-fold difference in gene expression was required in repeated comparisons of WT and Null cells and also in the comparison between Null+MYC cells and Null cells. These stringent inclusion criteria may exclude potentially real differences. For example, the gene expression differences for Cad in the three experiments were 2.81, 1.57, and 2.36 (ratios). Because the difference in one of the experiment is <2-fold cutoff (1.57), Cad was not considered positive.

(b) Some of the previously identified Myc target genes were found in different cellular systems and may not be regulated in the same manner as in the rat fibroblast cells.

(c) All of the previously reported c-Myc target genes were found in c-Myc overexpression systems. Cells may respond differently to overexpressed c-Myc than to physiologically expressed c-Myc. In fact, some of these discrepancies have been reported previously in other systems (3) .

c-Myc Regulates the Expression of Genes Involved in Protein Synthesis and Metabolism.
c-Myc has been considered an important regulator of the cell cycle machinery. We observed, however, that only a few cell cycle-associated genes were regulated by c-Myc. c-Myc up-regulates CDC2, PCNA, CKS2, AIM1, and DNA polymerase {alpha} but paradoxically down-regulates cyclin D1. Unexpectedly, however, we found that a majority of the c-Myc target genes (61 of 96 c-Myc-induced genes with known functions) are those involved in macromolecular synthesis, protein turnover, and metabolism (e.g., leucyl-tRNA synthetase, glycerate dehydrogenase, enolase, and lactate dehydrogenase, ubiquitin, E2-EPF ubiquitin-carrier protein, and heat shock proteins). Interestingly, the largest category of c-Myc-induced genes were those involved in protein synthesis, including 30 of the 43 distinct ribosomal protein genes present on our microarray. In addition to the 43 ribosomal protein genes, there are 20 other genes represented on our microarray involved in protein synthesis. Taken together, 57% of genes involved in protein synthesis (36 of 63) were identified as overexpressed, despite of the fact that these protein synthesis genes represented only 1.4% of the cDNAs on the microarray. It is, therefore, very unlikely that the induction of ribosomal/protein synthesis-associated genes by c-Myc is attributable to their overrepresentation on our microarray.

Because ribosomal genes are known to be up-regulated by cell growth, we sought to minimize the general effects of growth by comparing WT and Null cells under serum-starved conditions. In this state, c-Myc is also expressed at low levels in WT cells, as confirmed by Northern hybridization (Fig. 3)Citation . Twenty-nine genes differentially expressed between WT and Null cells during serum starvation overlapped with the c-Myc-responsive genes found in log phase (Tables 1Citation and 2)Citation . Among these 29 genes, 9 of 19 c-Myc up-regulated genes were ribosomal protein genes. Supporting these findings, recent studies have identified other genes involved in protein synthesis not represented in our arrays that appear to be regulated by c-Myc: eIF-2a, eIF4E, eIF5A, eIF4G, MrDb, nucleolin, isoleucine-tRNA synthetase, and ribosomal protein S11 (2 , 11) . Thus, an important function of c-Myc is in activating pathways of protein synthesis and metabolism in addition to cell cycle.

This conclusion is in concordance with results from recent genetic studies of c-myc in Drosophila [d-myc; (5) ]. The phenotype of the three d-myc mutants is remarkably similar to a group of Drosophila mutants named Minutes (5) . All molecularly characterized Minute mutants involve ribosomal protein genes (5) . The only reported candidate d-Myc target gene pit, a Drosophila homologue of MrDb in mammalian cells, is also involved in ribosome assembly and protein synthesis (12) . In addition to the evidence in Drosophila, the constitutively expressed c-myc transgene in mice and induced c-Myc expression in human B cells have also been found recently to increase protein synthesis (13 , 14) . These studies of c-Myc in Drosophila, mouse, and human would predict that the major c-Myc target genes involve protein synthesis and metabolism. Our findings support this prediction.

Overexpressed c-Myc Regulates Additional Set of Genes Compared with Physiologically Expressed c-Myc.
Because c-Myc overexpression is very common in human and animal cancers, we ectopically expressed c-Myc in WT cells (WT+MYC) and compared the gene expression between WT+MYC cells and WT cells during log-phase growth (Table 3)Citation . At log phase, WT cells had a sustained c-Myc expression, and the c-Myc expression in WT+MYC cells was ~4.5-fold higher than that in WT cells (Fig. 3Citation ; Table 3Citation ). We found that 32 known genes and 19 unknown genes were differentially expressed between WT+MYC cells and WT cells during log-phase growth. Forty-seven of these 51 genes uncovered here were not found in the comparison between log-phase WT cells and Null cells and may represent candidate genes responsive mainly to high levels of c-Myc expression. Among them, Gadd45 and thrombospondin have been reported previously as target genes of overexpressed c-Myc (2) . It is reasonable to hypothesize that the overexpressed c-Myc may turn on or off the expression of some genes not normally regulated by physiological levels of c-Myc either through direct effects on promoter occupancy or through the differential induction of other transcriptional activators.


View this table:
[in this window]
[in a new window]
  		Table 3 Genes regulated by overexpressed c-Myca

 
Recently, using oligonucleotide microarray analysis, Coller et al. (11) found 36 genes regulated by ectopically overexpressed c-Myc in density arrested or serum-starved human fibroblasts. Of these 36 c-Myc-regulated genes, 28 were not present on our rat cDNA microarray. Thus, direct comparisons between array results cannot be made. Nevertheless, of the other 8 genes present on both microarrays, tropomyosin, collagen, and HSP60 were also found in our study. Moreover, Coller et al. (11) also presented evidence for induction of some genes involved in protein synthesis and metabolism, although they did not show a predominance of ribosomal and protein synthesis gene induction as described herein. We suspect that the use of a primarily overexpression system involving a myc-ER construct, a different array system, and different growth conditions (arresting versus log-phase) may be the major reasons for the discrepancy.

That c-Myc up-regulates genes involved in protein synthesis may explain its role in carcinogenesis. In yeast, the ribosome assembly is precisely adjusted to the physiological demands of the cell, and the coordinated expression of ribosomal proteins is primarily regulated at the transcriptional level (15) . In human, several ribosomal proteins (L5, L21, L27a, L28, S5, S9, S10, and S29) have been shown to be overexpressed in colorectal carcinoma (16) . The increased expression of ribosomal protein S27 has been found in a wide variety of actively proliferating cells and tumor tissues, and its expression correlated with the degree of aggressiveness in prostate and colon malignancy (17 , 18) . Our results and the recent findings of others suggest that c-Myc may potentiate the sensitivity of cells to other mitogenic signals by preparing the protein synthesis machinery to meet the demand of cell proliferation.


View this table:
[in this window]
[in a new window]
  		Table 1A Continued

 

   ACKNOWLEDGMENTS
 
We are very grateful to J. Sedivy for c-myc null and wild-type cells. We thank Y. Fridell, L. Miller, L. Gangi, K. Zeller, and D. Petersen for technical help and L. Lee, J. Villa, O. Aprelikova, and B. Fang for helpful discussions.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 To whom requests for reprints should be addressed, at Division of Clinical Science, National Cancer Institute, Building 31, Room 3A11-MSC2440, Center Drive, Bethesda, MD 20892. Phone: (301) 496-3251; Fax: (301) 480-0313; E-mail: liue{at}nih.gov Back

2 The abbreviation used is: EST, expressed sequence tag. Back

3 Also accessible at www.tigr.org/tdb/ratarrays/index.html. A comprehensive listing of the genes matched, categories, and GenBank accession numbers of matched genes can be assessed at www.tigr.org/tdb/ratarrays. Back

4 Full lists are available at http://www-dcs.nci.nih.gov/research/labdata/Liulab. html. Back

Received 6/ 6/00. Accepted 9/15/00.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 

  1. Henriksson M., Luscher B. Proteins of the Myc network: essential regulators of cell growth and differentiation. Adv. Cancer Res., 68: 109-182, 1996.[Medline]
  2. Dang C. V. c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol. Cell. Biol., 19: 1-11, 1999.[Free Full Text]
  3. Bush A., Mateyak M., Dugan K., Obaya A., Adachi S., Sedivy J., Cole M. c-myc null cells misregulate cad and gadd45 but not other proposed c-Myc targets. Genes Dev., 12: 3797-3802, 1998.[Abstract/Free Full Text]
  4. Mateyak M. K., Obaya A. J., Adachi S., Sedivy J. M. Phenotypes of c-Myc-deficient rat fibroblasts isolated by targeted homologous recombination. Cell Growth Differ., 8: 1039-1048, 1997.[Abstract]
  5. Johnston L. A., Prober D. A., Edgar B. A., Eisenman R. N., Gallant P. Drosophila myc regulates cellular growth during development. Cell, 98: 779-790, 1999.[Medline]
  6. DeRisi J. L., Iyer V. R., Brown P. O. Exploring the metabolic and genetic control of gene expression on a genomic scale. Science (Washington DC), 278: 680-686, 1997.[Abstract/Free Full Text]
  7. Khan J., Simon R., Bittner M., Chen Y., Leighton S. B., Pohida T., Smith P. D., Jiang Y., Gooden G. C., Trent J. M., Meltzer P. S. Gene expression profiling of alveolar rhabdomyosarcoma with cDNA microarrays. Cancer Res., 58: 5009-5013, 1998.[Abstract/Free Full Text]
  8. Chen Y., Dougherty E. R., Bittner M. L. Ratio-based decisions and the quantitative analysis of cDNA microarray images. J. Biomed. Optics, 2: 364-374, 1997.
  9. Daksis J. I., Lu R. Y., Facchini L. M., Marhin W. W., Penn L. J. Myc induces cyclin D1 expression in the absence of de novo protein synthesis and links mitogen-stimulated signal transduction to the cell cycle. Oncogene, 9: 3635-3645, 1994.[Medline]
  10. Philipp A., Schneider A., Vasrik I., Finke K., Xiong Y., Beach D., Alitalo K., Eilers M. Repression of cyclin D1: a novel function of MYC. Mol. Cell. Biol., 14: 4032-4043, 1994.[Abstract/Free Full Text]
  11. Coller H. A., Grandori C., Tamayo P., Colbert T., Lander E. S., Eisenman R. N., Golub T. R. Expression analysis with oligonucleotide microarrays reveals that MYC regulates genes involved in growth, cell cycle, signaling, and adhesion. Proc. Natl. Acad. Sci. USA, 97: 3260-3265, 2000.[Abstract/Free Full Text]
  12. Zaffran S., Chartier A., Gallant P., Astier M., Arquier N., Doherty D., Gratecos D., Semeriva M. A Drosophila RNA helicase gene, pitchoune, is required for cell growth and proliferation and is a potential target of d-Myc. Development (Camb.), 125: 3571-3584, 1998.[Abstract]
  13. Iritani B. M., Eisenman R. N. c-Myc enhances protein synthesis and cell size during B lymphocyte development. Proc. Natl. Acad. Sci. USA, 96: 13180-13185, 1999.[Abstract/Free Full Text]
  14. Schuhmacher M., Staege M. S., Pajic A., Polack A., Weidle U. H., Bornkamm G. W., Eick D., Kohlhuber F. Control of cell growth by c-Myc in the absence of cell division. Curr. Biol., 9: 1255-1258, 1999.[Medline]
  15. Mager W. H., Planta R. J. Coordinate expression of ribosomal protein genes in yeast as a function of cellular growth rate. Mol. Cell. Biochem., 104: 181-187, 1991.[Medline]
  16. Frigerio J. M., Dagorn J. C., Iovanna J. L. Cloning, sequencing and expression of the L5, L21, L27a, L28, S5, S9, S10 and S29 human ribosomal protein mRNAs. Biochim. Biophys. Acta, 1262: 64-68, 1995.[Medline]
  17. Ganger D. R., Hamilton P. D., Fletcher J. W., Fernandez-Pol J. A. Metallopanstimulin is overexpressed in a patient with colonic carcinoma. Anticancer Res., 17: 1993-1999, 1997.[Medline]
  18. Fernandez-Pol J. A., Fletcher J. W., Hamilton P. D., Klos D. J. Expression of metallopanstimulin and oncogenesis in human prostatic carcinoma. Anticancer Res., 17: 1519-1530, 1997.[Medline]



This article has been cited by other articles:


Home page
 Cancer Res.Home page
C. M. Shachaf, A. J. Gentles, S. Elchuri, D. Sahoo, Y. Soen, O. Sharpe, O. D. Perez, M. Chang, D. Mitchel, W. H. Robinson, et al.
Genomic and Proteomic Analysis Reveals a Threshold Level of MYC Required for Tumor Maintenance
Cancer Res., July 1, 2008; 68(13): 5132 - 5142.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. ProteomicsHome page
L. M. Miller Jenkins, S. J. Mazur, M. Rossi, O. Gaidarenko, Y. Xu, and E. Appella
Quantitative Proteomics Analysis of the Effects of Ionizing Radiation in Wild Type and p53K317R Knock-in Mouse Thymocytes
Mol. Cell. Proteomics, April 1, 2008; 7(4): 716 - 727.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
F. Westermann, K.-O. Henrich, J. S. Wei, W. Lutz, M. Fischer, R. Konig, R. Wiedemeyer, V. Ehemann, B. Brors, K. Ernestus, et al.
High Skp2 Expression Characterizes High-Risk Neuroblastomas Independent of MYCN Status
Clin. Cancer Res., August 15, 2007; 13(16): 4695 - 4703.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
O. Delpuech, B. Griffiths, P. East, A. Essafi, E. W.-F. Lam, B. Burgering, J. Downward, and A. Schulze
Induction of Mxi1-SR{alpha} by FOXO3a Contributes to Repression of Myc-Dependent Gene Expression
Mol. Cell. Biol., July 1, 2007; 27(13): 4917 - 4930.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. GenomicsHome page
M. Bionaz and J. J. Loor
Identification of reference genes for quantitative real-time PCR in the bovine mammary gland during the lactation cycle
Physiol Genomics, May 11, 2007; 29(3): 312 - 319.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
J. Secombe, L. Li, L. Carlos, and R. N. Eisenman
The Trithorax group protein Lid is a trimethyl histone H3K4 demethylase required for dMyc-induced cell growth
Genes & Dev., March 1, 2007; 21(5): 537 - 551.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J. H. Patel and S. B. McMahon
BCL2 Is a Downstream Effector of MIZ-1 Essential for Blocking c-MYC-induced Apoptosis
J. Biol. Chem., January 5, 2007; 282(1): 5 - 13.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
C.-W. Yeh, S.-S. Huang, R.-P. Lee, and B. Y.-M. Yung
Ras-Dependent Recruitment of c-Myc for Transcriptional Activation of Nucleophosmin/B23 in Highly Malignant U1 Bladder Cancer Cells
Mol. Pharmacol., October 1, 2006; 70(4): 1443 - 1453.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
V. H. Cowling, S. Chandriani, M. L. Whitfield, and M. D. Cole
A Conserved Myc Protein Domain, MBIV, Regulates DNA Binding, Apoptosis, Transformation, and G2 Arrest.
Mol. Cell. Biol., June 1, 2006; 26(11): 4226 - 4239.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
E. R. Lawlor, L. Soucek, L. Brown-Swigart, K. Shchors, C. U. Bialucha, and G. I. Evan
Reversible Kinetic Analysis of Myc Targets In vivo Provides Novel Insights into Myc-Mediated Tumorigenesis.
Cancer Res., May 1, 2006; 66(9): 4591 - 4601.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Pathol.Home page
S Aulmann, N Adler, J Rom, B Helmchen, P Schirmacher, and H P Sinn
c-myc Amplifications in primary breast carcinomas and their local recurrences
J. Clin. Pathol., April 1, 2006; 59(4): 424 - 4248.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
M. Bredel, C. Bredel, D. Juric, G. R. Harsh, H. Vogel, L. D. Recht, and B. I. Sikic
Functional Network Analysis Reveals Extended Gliomagenesis Pathway Maps and Three Novel MYC-Interacting Genes in Human Gliomas
Cancer Res., October 1, 2005; 65(19): 8679 - 8689.
[Abstract] [Full Text] [PDF]

Home page
 J. Cell Biol.Home page
M. Holzel, M. Rohrmoser, M. Schlee, T. Grimm, T. Harasim, A. Malamoussi, A. Gruber-Eber, E. Kremmer, W. Hiddemann, G. W. Bornkamm, et al.
Mammalian WDR12 is a novel member of the Pes1-Bop1 complex and is required for ribosome biogenesis and cell proliferation
J. Cell Biol., August 1, 2005; 170(3): 367 - 378.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
F. Li, Y. Wang, K. I. Zeller, J. J. Potter, D. R. Wonsey, K. A. O'Donnell, J.-w. Kim, J. T. Yustein, L. A. Lee, and C. V. Dang
Myc Stimulates Nuclearly Encoded Mitochondrial Genes and Mitochondrial Biogenesis
Mol. Cell. Biol., July 15, 2005; 25(14): 6225 - 6234.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
A. Huang, C. S.W. Ho, R. Ponzielli, D. Barsyte-Lovejoy, E. Bouffet, D. Picard, C. E. Hawkins, and L. Z. Penn
Identification of a Novel c-Myc Protein Interactor, JPO2, with Transforming Activity in Medulloblastoma Cells
Cancer Res., July 1, 2005; 65(13): 5607 - 5619.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
E. Baena, A. Gandarillas, M. Vallespinos, J. Zanet, O. Bachs, C. Redondo, I. Fabregat, C. Martinez-A., and I. M. de Alboran
c-Myc regulates cell size and ploidy but is not essential for postnatal proliferation in liver
PNAS, May 17, 2005; 102(20): 7286 - 7291.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
L. J. Valentijn, A. Koppen, R. van Asperen, H. A. Root, F. Haneveld, and R. Versteeg
Inhibition of a New Differentiation Pathway in Neuroblastoma by Copy Number Defects of N-myc, Cdc42, and nm23 Genes
Cancer Res., April 15, 2005; 65(8): 3136 - 3145.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
K. Rothermund, K. Rogulski, E. Fernandes, A. Whiting, J. Sedivy, L. Pu, and E. V. Prochownik
C-Myc-Independent Restoration of Multiple Phenotypes by Two C-Myc Target Genes with Overlapping Functions
Cancer Res., March 15, 2005; 65(6): 2097 - 2107.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
C. Korgaonkar, J. Hagen, V. Tompkins, A. A. Frazier, C. Allamargot, F. W. Quelle, and D. E. Quelle
Nucleophosmin (B23) Targets ARF to Nucleoli and Inhibits Its Function
Mol. Cell. Biol., February 15, 2005; 25(4): 1258 - 1271.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
D. Marinkovic, T. Marinkovic, E. Kokai, T. Barth, P. Moller, and T. Wirth
Identification of novel Myc target genes with a potential role in lymphomagenesis
Nucleic Acids Res., October 11, 2004; 32(18): 5368 - 5378.
[Abstract] [Full Text] [PDF]

Home page
 DevelopmentHome page
S. B. Pierce, C. Yost, J. S. Britton, L. W. M. Loo, E. M. Flynn, B. A. Edgar, and R. N. Eisenman
dMyc is required for larval growth and endoreplication in Drosophila
Development, May 15, 2004; 131(10): 2317 - 2327.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
P. S. Kho, Z. Wang, L. Zhuang, Y. Li, J.-L. Chew, H.-H. Ng, E. T. Liu, and Q. Yu
p53-regulated Transcriptional Program Associated with Genotoxic Stress-induced Apoptosis
J. Biol. Chem., May 14, 2004; 279(20): 21183 - 21192.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S.-C. Teng, Y.-Y. Chen, Y.-N. Su, P.-C. Chou, Y.-C. Chiang, S.-F. Tseng, and K.-J. Wu
Direct Activation of HSP90A Transcription by c-Myc Contributes to c-Myc-induced Transformation
J. Biol. Chem., April 9, 2004; 279(15): 14649 - 14655.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
D. J. Murphy, L. B. Swigart, M. A. Israel, and G. I. Evan
Id2 Is Dispensable for Myc-Induced Epidermal Neoplasia
Mol. Cell. Biol., March 1, 2004; 24(5): 2083 - 2090.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
Z. Huang, J. A. Traugh, and J. M. Bishop
Negative Control of the Myc Protein by the Stress-Responsive Kinase Pak2
Mol. Cell. Biol., February 15, 2004; 24(4): 1582 - 1594.
[Abstract] [Full Text] [PDF]

Home page
 DevelopmentHome page
J. Z. Maines, L. M. Stevens, X. Tong, and D. Stein
Drosophila dMyc is required for ovary cell growth and endoreplication
Development, February 15, 2004; 131(4): 775 - 786.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. Lynch, C. Fitzgerald, K. A. Johnston, S. Wang, and E. V. Schmidt
Activated eIF4E-binding Protein Slows G1 Progression and Blocks Transformation by c-myc without Inhibiting Cell Growth
J. Biol. Chem., January 30, 2004; 279(5): 3327 - 3339.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
M. J. McConnell, N. Chevallier, W. Berkofsky-Fessler, J. M. Giltnane, R. B. Malani, L. M. Staudt, and J. D. Licht
Growth Suppression by Acute Promyelocytic Leukemia-Associated Protein PLZF Is Mediated by Repression of c-myc Expression
Mol. Cell. Biol., December 15, 2003; 23(24): 9375 - 9388.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
Z. Herceg, H. Li, C. Cuenin, V. Shukla, M. Radolf, P. Steinlein, and Z.-Q. Wang
Genome-wide analysis of gene expression regulated by the HAT cofactor Trrap in conditional knockout cells
Nucleic Acids Res., December 1, 2003; 31(23): 7011 - 7023.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
P. A. Clarke, M. L. George, S. Easdale, D. Cunningham, R. I. Swift, M. E. Hill, D. M. Tait, and P. Workman
Molecular Pharmacology of Cancer Therapy in Human Colorectal Cancer by Gene Expression Profiling
Cancer Res., October 15, 2003; 63(20): 6855 - 6863.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
I. Horikawa and J. C. Barrett
Transcriptional regulation of the telomerase hTERT gene as a target for cellular and viral oncogenic mechanisms
Carcinogenesis, July 1, 2003; 24(7): 1167 - 1176.
[Abstract] [Full Text] [PDF]

Home page
 DevelopmentHome page
M. Frye, C. Gardner, E. R. Li, I. Arnold, and F. M. Watt
Evidence that Myc activation depletes the epidermal stem cell compartment by modulating adhesive interactions with the local microenvironment
Development, June 15, 2003; 130(12): 2793 - 2808.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
F. Yi, R. Jaffe, and E. V. Prochownik
The CCL6 Chemokine Is Differentially Regulated by c-Myc and L-Myc, and Promotes Tumorigenesis and Metastasis
Cancer Res., June 1, 2003; 63(11): 2923 - 2932.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
A. Orian, B. van Steensel, J. Delrow, H. J. Bussemaker, L. Li, T. Sawado, E. Williams, L. W.M. Loo, S. M. Cowley, C. Yost, et al.
Genomic binding by the Drosophila Myc, Max, Mad/Mnt transcription factor network
Genes & Dev., May 1, 2003; 17(9): 1101 - 1114.
[Abstract] [Full Text] [PDF]

Home page