A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer

被引：148

作者：

Mello, Stephano S. ^{[1
]}

Valente, Liz J. ^{[1
]}

Raj, Nitin ^{[1
]}

Seoane, Jose A. ^{[2
,3
]}

Flowers, Brittany M. ^{[1
]}

McClendon, Jacob ^{[1
]}

Bieging-Rolett, Kathryn T. ^{[1
]}

Lee, Jonghyeob ^{[4
]}

Ivanochko, Danton ^{[5
,6
]}

Kozak, Margaret M. ^{[1
]}

Chang, Daniel T. ^{[1
,3
]}

Longacre, Teri A. ^{[3
,7
]}

Koong, Albert C. ^{[1
,3
,10
]}

Arrowsmith, Cheryl H. ^{[5
,6
]}

Kim, Seung K. ^{[2
,3
,4
]}

Vogel, Hannes ^{[3
,7
]}

Wood, Laura D. ^{[8
]}

Hruban, Ralph H. ^{[8
]}

Curtis, Christina ^{[2
,3
,9
]}

Attardi, Laura D. ^{[1
,3
,9
]}

机构：

[1] Stanford Univ, Dept Radiat Oncol, Sch Med, Stanford, CA 94305 USA

[2] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA

[3] Stanford Univ, Sch Med, Stanford Canc Inst, Stanford, CA 94305 USA

[4] Stanford Univ, Dept Dev Biol, Sch Med, Stanford, CA 94305 USA

[5] Univ Toronto, Struct Genom Consortium, Princess Margaret Canc Ctr, Toronto, ON, Canada

[6] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada

[7] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA

[8] Johns Hopkins Univ, Sch Med, Dept Pathol, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD 21205 USA

[9] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA

[10] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA

来源：

CANCER CELL | 2017年 / 32卷 / 04期

基金：

加拿大自然科学与工程研究理事会;

关键词：

HIPPO PATHWAY; DUCTAL ADENOCARCINOMA; K-RAS; ACTIVATION; PROGRESSION; COOPERATE; COMPLEX; YAP/TAZ; YAP; IDENTIFICATION;

D O I：

10.1016/j.ccell.2017.09.007

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The p53 transcription factor is a critical barrier to pancreatic cancer progression. To unravel mechanisms of p53-mediated tumor suppression, which have remained elusive, we analyzed pancreatic cancer development in mice expressing p53 transcriptional activation domain (TAD) mutants. Surprisingly, the p53 53,54 TAD2 mutant behaves as a "super-tumor suppressor,'' with an enhanced capacity to both suppress pancreatic cancer and transactivate select p53 target genes, including Ptpn14. Ptpn14 encodes a negative regulator of the Yap oncoprotein and is necessary and sufficient for pancreatic cancer suppression, like p53. We show that p53 deficiency promotes Yap signaling and that PTPN14 and TP53 mutations are mutually exclusive in human cancers. These studies uncover a p53-Ptpn14-Yap pathway that is integral to p53-mediated tumor suppression.

引用

页码：460 / +

页数：20

共 70 条

[1] Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma [J].

Aguirre, AJ ;

Bardeesy, N ;

Sinha, M ;

Lopez, L ;

Tuveson, DA ;

Horner, J ;

Redston, MS ;

DePinho, RA .

GENES & DEVELOPMENT, 2003, 17 (24) :3112-3126

[2]

[Anonymous], PERSPECT MED

[3] A positive feedback loop between the p53 and Lats2 tumor suppressors prevents tetraploidization [J].

Aylon, Yael ;

Michael, Dan ;

Shmueli, Ayelet ;

Yabuta, Norikazu ;

Nojima, Hiroshi ;

Oren, Moshe .

GENES & DEVELOPMENT, 2006, 20 (19) :2687-2700

[4] Both p16Ink4a and the p19Arf-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse [J].

Bardeesy, N ;

Aguirre, AJ ;

Chu, GC ;

Cheng, KH ;

Lopez, LV ;

Hezel, AF ;

Feng, B ;

Brennan, C ;

Weissleder, R ;

Mahmood, U ;

Hanahan, D ;

Redston, MS ;

Chin, L ;

DePinho, RA .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (15) :5947-5952

[5] Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer [J].

Bardeesy, Nabeel ;

Cheng, Kuang-hung ;

Berger, Justin H. ;

Chu, Gerald C. ;

Pahler, Jessica ;

Olson, Peter ;

Hezel, Aram F. ;

Horner, James ;

Lauwers, Gregory Y. ;

Hanahan, Douglas ;

DePinho, Ronald A. .

GENES & DEVELOPMENT, 2006, 20 (22) :3130-3146

[6] Genomic Instability at Both the Base Pair Level and the Chromosomal Level Is Detectable in Earliest PanIN Lesions in Tissues of Chronic Pancreatitis [J].

Baumgart, Mario ;

Werther, Meike ;

Bockholt, Anke ;

Scheurer, Maria ;

Rueschoff, Josef ;

Dietmaier, Wolfgang ;

Ghadimi, B. Michael ;

Heinmoeller, Ernst .

PANCREAS, 2010, 39 (07) :1093-1103

[7] Unravelling mechanisms of p53-mediated tumour suppression [J].

Bieging, Kathryn T. ;

Mello, Stephano Spano ;

Attardi, Laura D. .

NATURE REVIEWS CANCER, 2014, 14 (05) :359-370

[8] Genomic analysis identifies new drivers and progression pathways in skin basal cell carcinoma [J].

Bonilla, Ximena ;

Parmentier, Laurent ;

King, Bryan ;

Bezrukov, Fedor ;

Kaya, Gurkan ;

Zoete, Vincent ;

Seplyarskiy, Vladimir B. ;

Sharpe, Hayley J. ;

McKee, Thomas ;

Letourneau, Audrey ;

Ribaux, Pascale G. ;

Popadin, Konstantin ;

Basset-Seguin, Nicole ;

Ben Chaabene, Rouaa ;

Santoni, Federico A. ;

Andrianova, Maria A. ;

Guipponi, Michel ;

Garieri, Marco ;

Verdan, Carole ;

Grosdemange, Kerstin ;

Sumara, Olga ;

Eilers, Martin ;

Aifantis, Iannis ;

Michielin, Olivier ;

de Sauvage, Frederic J. ;

Antonarakis, Stylianos E. ;

Nikolaev, Sergey I. .

NATURE GENETICS, 2016, 48 (04) :398-+

[9] Distinct p53 Transcriptional Programs Dictate Acute DNA-Damage Responses and Tumor Suppression [J].

Brady, Colleen A. ;

Jiang, Dadi ;

Mello, Stephano S. ;

Johnson, Thomas M. ;

Jarvis, Lesley A. ;

Kozak, Margaret M. ;

Broz, Daniela Kenzelmann ;

Basak, Shashwati ;

Park, Eunice J. ;

McLaughlin, Margaret E. ;

Karnezis, Anthony N. ;

Attardi, Laura D. .

CELL, 2011, 145 (04) :571-583

[10] p53 at a glance [J].

Brady, Colleen A. ;

Attardi, Laura D. .

JOURNAL OF CELL SCIENCE, 2010, 123 (15) :2527-2532

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