SP/KLF (Specificity protein/Krüppel-like factor) transcription factors comprise an emerging group of proteins that may behave as tumour suppressors. Incidentally, many cancers that display alterations in certain KLF proteins are also associated with a high incidence of KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue) mutations. Therefore in the present paper we investigate whether SP/KLF proteins suppress KRAS-mediated cell growth, and more importantly, the potential mechanisms underlying these effects. Using a comprehensive family-wide screening of the 24 SP/KLF members, we discovered that SP5, SP8, KLF2, KLF3, KLF4, KLF11, KLF13, KLF14, KLF15 and KLF16 inhibit cellular growth and suppress transformation mediated by oncogenic KRAS. Each protein in this subset of SP/KLF members individually inhibits BrdU (5-bromo-2-deoxyuridine) incorporation in KRAS oncogenic-mutant cancer cells. SP5, KLF3, KLF11, KLF13, KLF14 and KLF16 also increase apoptosis in these cells. Using KLF11 as a representative model for mechanistic studies, we demonstrate that this protein inhibits the ability of cancer cells to form both colonies in soft agar and tumour growth in vivo. Molecular studies demonstrate that these effects of KLF11 are mediated, at least in part, through silencing cyclin A via binding to its promoter and leading to cell-cycle arrest in S-phase. Interestingly, similar to KLF11, KLF14 and KLF16 mechanistically share the ability to modulate the expression of cyclin A. Collectively, the present study stringently defines a distinct subset of SP/KLF proteins that impairs KRAS-mediated cell growth, and that mechanistically some members of this subset accomplish this, at least in part, through regulation of the cyclin A promoter.
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Research Article|
March 29 2011
A functional family-wide screening of SP/KLF proteins identifies a subset of suppressors of KRAS-mediated cell growth
Martin E. Fernandez-Zapico;
Martin E. Fernandez-Zapico
1
*Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55901, U.S.A.
†Schulze Center for Novel Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55901, U.S.A.
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Gwen A. Lomberk;
Gwen A. Lomberk
1
*Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55901, U.S.A.
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Shoichiro Tsuji;
Shoichiro Tsuji
*Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55901, U.S.A.
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Cathrine J. DeMars;
Cathrine J. DeMars
*Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55901, U.S.A.
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Michael R. Bardsley;
Michael R. Bardsley
*Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55901, U.S.A.
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Yi-Hui Lin;
Yi-Hui Lin
†Schulze Center for Novel Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55901, U.S.A.
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Luciana L. Almada;
Luciana L. Almada
†Schulze Center for Novel Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55901, U.S.A.
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Jing-Jing Han;
Jing-Jing Han
*Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55901, U.S.A.
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Debabrata Mukhopadhyay;
Debabrata Mukhopadhyay
‡Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55901, U.S.A.
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Tamas Ordog;
Tamas Ordog
*Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55901, U.S.A.
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Navtej S. Buttar;
Navtej S. Buttar
*Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55901, U.S.A.
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Raul Urrutia
Raul Urrutia
2
*Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55901, U.S.A.
‡Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55901, U.S.A.
2To whom correspondence should be addressed (email urrutia.raul@mayo.edu).
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Publisher: Portland Press Ltd
Received:
May 25 2010
Revision Received:
December 16 2010
Accepted:
December 20 2010
Accepted Manuscript online:
December 20 2010
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem J (2011) 435 (2): 529–537.
Article history
Received:
May 25 2010
Revision Received:
December 16 2010
Accepted:
December 20 2010
Accepted Manuscript online:
December 20 2010
Citation
Martin E. Fernandez-Zapico, Gwen A. Lomberk, Shoichiro Tsuji, Cathrine J. DeMars, Michael R. Bardsley, Yi-Hui Lin, Luciana L. Almada, Jing-Jing Han, Debabrata Mukhopadhyay, Tamas Ordog, Navtej S. Buttar, Raul Urrutia; A functional family-wide screening of SP/KLF proteins identifies a subset of suppressors of KRAS-mediated cell growth. Biochem J 15 April 2011; 435 (2): 529–537. doi: https://doi.org/10.1042/BJ20100773
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