Transactivation of miR-34a by p53 Broadly Influences Gene Expression and Promotes Apoptosis

Tsung Cheng Chang; Erik A. Wentzel; Oliver A. Kent; Kalyani Ramachandran; Michael Mullendore; Kwang Hyuck Lee; Georg Feldmann; Munekazu Yamakuchi; Marcella Ferlito; Charles J. Lowenstein; Dan E E. Arking; Michael A. Beer; Anirban Maitra; Joshua T. Mendell

doi:10.1016/j.molcel.2007.05.010

Transactivation of miR-34a by p53 Broadly Influences Gene Expression and Promotes Apoptosis

Tsung Cheng Chang, Erik A. Wentzel, Oliver A. Kent, Kalyani Ramachandran, Michael Mullendore, Kwang Hyuck Lee, Georg Feldmann, Munekazu Yamakuchi, Marcella Ferlito, Charles J. Lowenstein, Dan E E. Arking, Michael A. Beer, Anirban Maitra, Joshua T. Mendell

School of Medicine

Research output: Contribution to journal › Article › peer-review

1614 Scopus citations

Abstract

The p53 tumor suppressor protein is a critical regulator of the cellular response to cancer-initiating insults such as genotoxic stress. In this report, we demonstrate that microRNAs (miRNAs) are important components of the p53 transcriptional network. Global miRNA expression analyses identified a cohort of miRNAs that exhibit p53-dependent upregulation following DNA damage. One such miRNA, miR-34a, is commonly deleted in human cancers and, as shown here, frequently absent in pancreatic cancer cells. Characterization of the miR-34a primary transcript and promoter demonstrates that this miRNA is directly transactivated by p53. Expression of miR-34a causes dramatic reprogramming of gene expression and promotes apoptosis. Much like the known set of p53-regulated genes, miR-34a-responsive genes are highly enriched for those that regulate cell-cycle progression, apoptosis, DNA repair, and angiogenesis. Therefore, it is likely that an important function of miR-34a is the modulation and fine-tuning of the gene expression program initiated by p53.

Original language	English (US)
Pages (from-to)	745-752
Number of pages	8
Journal	Molecular cell
Volume	26
Issue number	5
DOIs	https://doi.org/10.1016/j.molcel.2007.05.010
State	Published - Jun 8 2007

Keywords

CELLCYCLE
RNA

ASJC Scopus subject areas

Molecular Biology
Cell Biology

Access to Document

10.1016/j.molcel.2007.05.010

Cite this

Chang, T. C., Wentzel, E. A., Kent, O. A., Ramachandran, K., Mullendore, M., Lee, KH., Feldmann, G., Yamakuchi, M., Ferlito, M., Lowenstein, C. J., Arking, DE. E., Beer, M. A., Maitra, A., & Mendell, J. T. (2007). Transactivation of miR-34a by p53 Broadly Influences Gene Expression and Promotes Apoptosis. Molecular cell, 26(5), 745-752. https://doi.org/10.1016/j.molcel.2007.05.010

Chang, TC, Wentzel, EA, Kent, OA, Ramachandran, K, Mullendore, M, Lee, KH, Feldmann, G, Yamakuchi, M, Ferlito, M, Lowenstein, CJ , Arking, DEE , Beer, MA, Maitra, A & Mendell, JT 2007, 'Transactivation of miR-34a by p53 Broadly Influences Gene Expression and Promotes Apoptosis', Molecular cell, vol. 26, no. 5, pp. 745-752. https://doi.org/10.1016/j.molcel.2007.05.010

@article{27731bdd65cc4d8ab583bb01e3749ad7,

title = "Transactivation of miR-34a by p53 Broadly Influences Gene Expression and Promotes Apoptosis",

abstract = "The p53 tumor suppressor protein is a critical regulator of the cellular response to cancer-initiating insults such as genotoxic stress. In this report, we demonstrate that microRNAs (miRNAs) are important components of the p53 transcriptional network. Global miRNA expression analyses identified a cohort of miRNAs that exhibit p53-dependent upregulation following DNA damage. One such miRNA, miR-34a, is commonly deleted in human cancers and, as shown here, frequently absent in pancreatic cancer cells. Characterization of the miR-34a primary transcript and promoter demonstrates that this miRNA is directly transactivated by p53. Expression of miR-34a causes dramatic reprogramming of gene expression and promotes apoptosis. Much like the known set of p53-regulated genes, miR-34a-responsive genes are highly enriched for those that regulate cell-cycle progression, apoptosis, DNA repair, and angiogenesis. Therefore, it is likely that an important function of miR-34a is the modulation and fine-tuning of the gene expression program initiated by p53.",

keywords = "CELLCYCLE, RNA",

author = "Chang, {Tsung Cheng} and Wentzel, {Erik A.} and Kent, {Oliver A.} and Kalyani Ramachandran and Michael Mullendore and Kwang Hyuck Lee and Georg Feldmann and Munekazu Yamakuchi and Marcella Ferlito and Lowenstein, {Charles J.} and Arking, {Dan E E.} and Beer, {Michael A.} and Anirban Maitra and Mendell, {Joshua T.}",

note = "Funding Information: The authors wish to thank Bert Vogelstein for HCT116 p53 WT and p53 −/− cells, Garry Nolan for Phoenix cells, Michael Thomson and Scott Hammond for assistance with miRNA arrays, and Francisco Martinez Murillo and Chunfa Jie for assistance with the Affymetrix microarray experiments. This work was supported by a Rita Allen Foundation Scholar Award (J.T.M.), the Lustgarten Foundation for Pancreatic Cancer Research (J.T.M), the Sol Goldman Pancreatic Cancer Research Center (A.M.), and the National Cancer Institute (R01CA120185 and R01CA113669). ",

year = "2007",

month = jun,

day = "8",

doi = "10.1016/j.molcel.2007.05.010",

language = "English (US)",

volume = "26",

pages = "745--752",

journal = "Molecular cell",

issn = "1097-2765",

publisher = "Cell Press",

number = "5",

}

TY - JOUR

T1 - Transactivation of miR-34a by p53 Broadly Influences Gene Expression and Promotes Apoptosis

AU - Chang, Tsung Cheng

AU - Wentzel, Erik A.

AU - Kent, Oliver A.

AU - Ramachandran, Kalyani

AU - Mullendore, Michael

AU - Lee, Kwang Hyuck

AU - Feldmann, Georg

AU - Yamakuchi, Munekazu

AU - Ferlito, Marcella

AU - Lowenstein, Charles J.

AU - Arking, Dan E E.

AU - Beer, Michael A.

AU - Maitra, Anirban

AU - Mendell, Joshua T.

N1 - Funding Information: The authors wish to thank Bert Vogelstein for HCT116 p53 WT and p53 −/− cells, Garry Nolan for Phoenix cells, Michael Thomson and Scott Hammond for assistance with miRNA arrays, and Francisco Martinez Murillo and Chunfa Jie for assistance with the Affymetrix microarray experiments. This work was supported by a Rita Allen Foundation Scholar Award (J.T.M.), the Lustgarten Foundation for Pancreatic Cancer Research (J.T.M), the Sol Goldman Pancreatic Cancer Research Center (A.M.), and the National Cancer Institute (R01CA120185 and R01CA113669).

PY - 2007/6/8

Y1 - 2007/6/8

N2 - The p53 tumor suppressor protein is a critical regulator of the cellular response to cancer-initiating insults such as genotoxic stress. In this report, we demonstrate that microRNAs (miRNAs) are important components of the p53 transcriptional network. Global miRNA expression analyses identified a cohort of miRNAs that exhibit p53-dependent upregulation following DNA damage. One such miRNA, miR-34a, is commonly deleted in human cancers and, as shown here, frequently absent in pancreatic cancer cells. Characterization of the miR-34a primary transcript and promoter demonstrates that this miRNA is directly transactivated by p53. Expression of miR-34a causes dramatic reprogramming of gene expression and promotes apoptosis. Much like the known set of p53-regulated genes, miR-34a-responsive genes are highly enriched for those that regulate cell-cycle progression, apoptosis, DNA repair, and angiogenesis. Therefore, it is likely that an important function of miR-34a is the modulation and fine-tuning of the gene expression program initiated by p53.

AB - The p53 tumor suppressor protein is a critical regulator of the cellular response to cancer-initiating insults such as genotoxic stress. In this report, we demonstrate that microRNAs (miRNAs) are important components of the p53 transcriptional network. Global miRNA expression analyses identified a cohort of miRNAs that exhibit p53-dependent upregulation following DNA damage. One such miRNA, miR-34a, is commonly deleted in human cancers and, as shown here, frequently absent in pancreatic cancer cells. Characterization of the miR-34a primary transcript and promoter demonstrates that this miRNA is directly transactivated by p53. Expression of miR-34a causes dramatic reprogramming of gene expression and promotes apoptosis. Much like the known set of p53-regulated genes, miR-34a-responsive genes are highly enriched for those that regulate cell-cycle progression, apoptosis, DNA repair, and angiogenesis. Therefore, it is likely that an important function of miR-34a is the modulation and fine-tuning of the gene expression program initiated by p53.

KW - CELLCYCLE

KW - RNA

UR - http://www.scopus.com/inward/record.url?scp=34249817549&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34249817549&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2007.05.010

DO - 10.1016/j.molcel.2007.05.010

M3 - Article

C2 - 17540599

AN - SCOPUS:34249817549

SN - 1097-2765

VL - 26

SP - 745

EP - 752

JO - Molecular cell

JF - Molecular cell

IS - 5

ER -