The Six1 oncoprotein downregulates p53 via concomitant regulation of RPL26 and microRNA-27a-3p

Christina G. Towers, Anna L. Guarnieri, Doug S. Micalizzi, J. Chuck Harrell, Austin E. Gillen, Jihye Kim, Chu An Wang, Michael U.J. Oliphant, David J. Drasin, Michelle A. Guney, Peter Kabos, Carol A. Sartorius, Aik Choon Tan, Charles M. Perou, Joaquin M. Espinosa, Heide L. Ford

研究成果: Article

20 引文 (Scopus)

摘要

TP53 is mutated in 50% of all cancers, and its function is often compromised in cancers where it is not mutated. Here we demonstrate that the pro-tumorigenic/metastatic Six1 homeoprotein decreases p53 levels through a mechanism that does not involve the negative regulator of p53, MDM2. Instead, Six1 regulates p53 via a dual mechanism involving upregulation of microRNA-27a and downregulation of ribosomal protein L26 (RPL26). Mutation analysis confirms that RPL26 inhibits miR-27a binding and prevents microRNA-mediated downregulation of p53. The clinical relevance of this interaction is underscored by the finding that Six1 expression strongly correlates with decreased RPL26 across numerous tumour types. Importantly, we find that Six1 expression leads to marked resistance to therapies targeting the p53-MDM2 interaction. Thus, we identify a competitive mechanism of p53 regulation, which may have consequences for drugs aimed at reinstating p53 function in tumours.

原文English
文章編號10077
期刊Nature communications
6
DOIs
出版狀態Published - 2015 十二月 21

指紋

Tumor Suppressor Protein p53
Ribosomal Proteins
Oncogene Proteins
MicroRNAs
Down-Regulation
proteins
Tumors
tumors
cancer
Homeodomain Proteins
Neoplasms
regulators
mutations
therapy
drugs
interactions
Up-Regulation
Pharmaceutical Preparations
Mutation

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

引用此文

Towers, C. G., Guarnieri, A. L., Micalizzi, D. S., Harrell, J. C., Gillen, A. E., Kim, J., ... Ford, H. L. (2015). The Six1 oncoprotein downregulates p53 via concomitant regulation of RPL26 and microRNA-27a-3p. Nature communications, 6, [10077]. https://doi.org/10.1038/ncomms10077
Towers, Christina G. ; Guarnieri, Anna L. ; Micalizzi, Doug S. ; Harrell, J. Chuck ; Gillen, Austin E. ; Kim, Jihye ; Wang, Chu An ; Oliphant, Michael U.J. ; Drasin, David J. ; Guney, Michelle A. ; Kabos, Peter ; Sartorius, Carol A. ; Tan, Aik Choon ; Perou, Charles M. ; Espinosa, Joaquin M. ; Ford, Heide L. / The Six1 oncoprotein downregulates p53 via concomitant regulation of RPL26 and microRNA-27a-3p. 於: Nature communications. 2015 ; 卷 6.
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abstract = "TP53 is mutated in 50{\%} of all cancers, and its function is often compromised in cancers where it is not mutated. Here we demonstrate that the pro-tumorigenic/metastatic Six1 homeoprotein decreases p53 levels through a mechanism that does not involve the negative regulator of p53, MDM2. Instead, Six1 regulates p53 via a dual mechanism involving upregulation of microRNA-27a and downregulation of ribosomal protein L26 (RPL26). Mutation analysis confirms that RPL26 inhibits miR-27a binding and prevents microRNA-mediated downregulation of p53. The clinical relevance of this interaction is underscored by the finding that Six1 expression strongly correlates with decreased RPL26 across numerous tumour types. Importantly, we find that Six1 expression leads to marked resistance to therapies targeting the p53-MDM2 interaction. Thus, we identify a competitive mechanism of p53 regulation, which may have consequences for drugs aimed at reinstating p53 function in tumours.",
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Towers, CG, Guarnieri, AL, Micalizzi, DS, Harrell, JC, Gillen, AE, Kim, J, Wang, CA, Oliphant, MUJ, Drasin, DJ, Guney, MA, Kabos, P, Sartorius, CA, Tan, AC, Perou, CM, Espinosa, JM & Ford, HL 2015, 'The Six1 oncoprotein downregulates p53 via concomitant regulation of RPL26 and microRNA-27a-3p', Nature communications, 卷 6, 10077. https://doi.org/10.1038/ncomms10077

The Six1 oncoprotein downregulates p53 via concomitant regulation of RPL26 and microRNA-27a-3p. / Towers, Christina G.; Guarnieri, Anna L.; Micalizzi, Doug S.; Harrell, J. Chuck; Gillen, Austin E.; Kim, Jihye; Wang, Chu An; Oliphant, Michael U.J.; Drasin, David J.; Guney, Michelle A.; Kabos, Peter; Sartorius, Carol A.; Tan, Aik Choon; Perou, Charles M.; Espinosa, Joaquin M.; Ford, Heide L.

於: Nature communications, 卷 6, 10077, 21.12.2015.

研究成果: Article

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T1 - The Six1 oncoprotein downregulates p53 via concomitant regulation of RPL26 and microRNA-27a-3p

AU - Towers, Christina G.

AU - Guarnieri, Anna L.

AU - Micalizzi, Doug S.

AU - Harrell, J. Chuck

AU - Gillen, Austin E.

AU - Kim, Jihye

AU - Wang, Chu An

AU - Oliphant, Michael U.J.

AU - Drasin, David J.

AU - Guney, Michelle A.

AU - Kabos, Peter

AU - Sartorius, Carol A.

AU - Tan, Aik Choon

AU - Perou, Charles M.

AU - Espinosa, Joaquin M.

AU - Ford, Heide L.

PY - 2015/12/21

Y1 - 2015/12/21

N2 - TP53 is mutated in 50% of all cancers, and its function is often compromised in cancers where it is not mutated. Here we demonstrate that the pro-tumorigenic/metastatic Six1 homeoprotein decreases p53 levels through a mechanism that does not involve the negative regulator of p53, MDM2. Instead, Six1 regulates p53 via a dual mechanism involving upregulation of microRNA-27a and downregulation of ribosomal protein L26 (RPL26). Mutation analysis confirms that RPL26 inhibits miR-27a binding and prevents microRNA-mediated downregulation of p53. The clinical relevance of this interaction is underscored by the finding that Six1 expression strongly correlates with decreased RPL26 across numerous tumour types. Importantly, we find that Six1 expression leads to marked resistance to therapies targeting the p53-MDM2 interaction. Thus, we identify a competitive mechanism of p53 regulation, which may have consequences for drugs aimed at reinstating p53 function in tumours.

AB - TP53 is mutated in 50% of all cancers, and its function is often compromised in cancers where it is not mutated. Here we demonstrate that the pro-tumorigenic/metastatic Six1 homeoprotein decreases p53 levels through a mechanism that does not involve the negative regulator of p53, MDM2. Instead, Six1 regulates p53 via a dual mechanism involving upregulation of microRNA-27a and downregulation of ribosomal protein L26 (RPL26). Mutation analysis confirms that RPL26 inhibits miR-27a binding and prevents microRNA-mediated downregulation of p53. The clinical relevance of this interaction is underscored by the finding that Six1 expression strongly correlates with decreased RPL26 across numerous tumour types. Importantly, we find that Six1 expression leads to marked resistance to therapies targeting the p53-MDM2 interaction. Thus, we identify a competitive mechanism of p53 regulation, which may have consequences for drugs aimed at reinstating p53 function in tumours.

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DO - 10.1038/ncomms10077

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Towers CG, Guarnieri AL, Micalizzi DS, Harrell JC, Gillen AE, Kim J 等. The Six1 oncoprotein downregulates p53 via concomitant regulation of RPL26 and microRNA-27a-3p. Nature communications. 2015 12月 21;6. 10077. https://doi.org/10.1038/ncomms10077