p16( INK4a) positively regulates cyclin D1 and E2F1 through negative control of AUF1.

<h4>Background</h4>The cyclin-D/CDK4,6/p16(INK4a)/pRB/E2F pathway, a key regulator of the critical G1 to S phase transition of the cell cycle, is universally disrupted in human cancer. However, the precise function of the different members of this pathway and their functional interplay a...

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Autores principales:	Huda H Al-Khalaf, Dilek Colak, Maher Al-Saif, Albandary Al-Bakheet, Siti-Faujiah Hendrayani, Nujoud Al-Yousef, Namik Kaya, Khalid S Khabar, Abdelilah Aboussekhra
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d7f9ff83f9be405ab2aa0df2055b4300
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spelling	oai:doaj.org-article:d7f9ff83f9be405ab2aa0df2055b43002021-11-18T06:49:55Zp16( INK4a) positively regulates cyclin D1 and E2F1 through negative control of AUF1.1932-620310.1371/journal.pone.0021111https://doaj.org/article/d7f9ff83f9be405ab2aa0df2055b43002011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21799732/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>The cyclin-D/CDK4,6/p16(INK4a)/pRB/E2F pathway, a key regulator of the critical G1 to S phase transition of the cell cycle, is universally disrupted in human cancer. However, the precise function of the different members of this pathway and their functional interplay are still not well defined.<h4>Methodology/principal findings</h4>We have shown here that the tumor suppressor p16(INK4a) protein positively controls the expression of cyclin D1 and E2F1 in both human and mouse cells. p16(INK4a) stabilizes the mRNAs of the corresponding genes through negative regulation of the mRNA decay-promoting AUF1 protein. Immunoprecipitation of AUF1-associated RNAs followed by RT-PCR indicated that endogenous AUF1 binds to the cyclin D1 and E2F1 mRNAs. Furthermore, AUF1 down-regulation increased the expression levels of these genes, while concurrent silencing of AUF1 and p16(INK4a), using specific siRNAs, restored normal expression of both cyclinD1 and E2F1. Besides, we have shown the presence of functional AU-rich elements in the E2F1 3'UTR, which contributed to p16/AUF1-mediated regulation of E2F1 post-transcriptional events in vivo. Importantly, genome-wide gene expression microarray analysis revealed the presence of a large number of genes differentially expressed in a p16(INK4a) -dependent manner, and several of these genes are also members of the AUF1 and E2F1 regulons. We also present evidence that E2F1 mediates p16-dependent regulation of several pro- and anti-apoptotic proteins, and the consequent induction of spontaneous as well as doxorubicin-induced apoptosis.<h4>Conclusion/significance</h4>These findings show that the cyclin-dependent kinase inhibitor p16( INK4a) is also a modulator of transcription and apoptosis through controlling the expression of two major transcription regulators, AUF1 and E2F1.Huda H Al-KhalafDilek ColakMaher Al-SaifAlbandary Al-BakheetSiti-Faujiah HendrayaniNujoud Al-YousefNamik KayaKhalid S KhabarAbdelilah AboussekhraPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 7, p e21111 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Huda H Al-Khalaf Dilek Colak Maher Al-Saif Albandary Al-Bakheet Siti-Faujiah Hendrayani Nujoud Al-Yousef Namik Kaya Khalid S Khabar Abdelilah Aboussekhra p16( INK4a) positively regulates cyclin D1 and E2F1 through negative control of AUF1.
description	<h4>Background</h4>The cyclin-D/CDK4,6/p16(INK4a)/pRB/E2F pathway, a key regulator of the critical G1 to S phase transition of the cell cycle, is universally disrupted in human cancer. However, the precise function of the different members of this pathway and their functional interplay are still not well defined.<h4>Methodology/principal findings</h4>We have shown here that the tumor suppressor p16(INK4a) protein positively controls the expression of cyclin D1 and E2F1 in both human and mouse cells. p16(INK4a) stabilizes the mRNAs of the corresponding genes through negative regulation of the mRNA decay-promoting AUF1 protein. Immunoprecipitation of AUF1-associated RNAs followed by RT-PCR indicated that endogenous AUF1 binds to the cyclin D1 and E2F1 mRNAs. Furthermore, AUF1 down-regulation increased the expression levels of these genes, while concurrent silencing of AUF1 and p16(INK4a), using specific siRNAs, restored normal expression of both cyclinD1 and E2F1. Besides, we have shown the presence of functional AU-rich elements in the E2F1 3'UTR, which contributed to p16/AUF1-mediated regulation of E2F1 post-transcriptional events in vivo. Importantly, genome-wide gene expression microarray analysis revealed the presence of a large number of genes differentially expressed in a p16(INK4a) -dependent manner, and several of these genes are also members of the AUF1 and E2F1 regulons. We also present evidence that E2F1 mediates p16-dependent regulation of several pro- and anti-apoptotic proteins, and the consequent induction of spontaneous as well as doxorubicin-induced apoptosis.<h4>Conclusion/significance</h4>These findings show that the cyclin-dependent kinase inhibitor p16( INK4a) is also a modulator of transcription and apoptosis through controlling the expression of two major transcription regulators, AUF1 and E2F1.
format	article
author	Huda H Al-Khalaf Dilek Colak Maher Al-Saif Albandary Al-Bakheet Siti-Faujiah Hendrayani Nujoud Al-Yousef Namik Kaya Khalid S Khabar Abdelilah Aboussekhra
author_facet	Huda H Al-Khalaf Dilek Colak Maher Al-Saif Albandary Al-Bakheet Siti-Faujiah Hendrayani Nujoud Al-Yousef Namik Kaya Khalid S Khabar Abdelilah Aboussekhra
author_sort	Huda H Al-Khalaf
title	p16( INK4a) positively regulates cyclin D1 and E2F1 through negative control of AUF1.
title_short	p16( INK4a) positively regulates cyclin D1 and E2F1 through negative control of AUF1.
title_full	p16( INK4a) positively regulates cyclin D1 and E2F1 through negative control of AUF1.
title_fullStr	p16( INK4a) positively regulates cyclin D1 and E2F1 through negative control of AUF1.
title_full_unstemmed	p16( INK4a) positively regulates cyclin D1 and E2F1 through negative control of AUF1.
title_sort	p16( ink4a) positively regulates cyclin d1 and e2f1 through negative control of auf1.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/d7f9ff83f9be405ab2aa0df2055b4300
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p16( INK4a) positively regulates cyclin D1 and E2F1 through negative control of AUF1.

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