A Mutant-p53/Smad Complex Opposes p63 to Empower TGFβ-Induced Metastasis

被引：675

作者：

Adorno, Maddalena ^{[1
]}

Cordenonsi, Michelangelo ^{[1
]}

Montagner, Marco ^{[1
]}

Dupont, Sirio ^{[1
]}

Wong, Christine ^{[2
]}

Hann, Byron ^{[2
]}

Solari, Aldo ^{[3
]}

Bobisse, Sara ^{[4
,5
]}

Rondina, Maria Beatrice ^{[4
,5
]}

Guzzardo, Vincenza ^{[6
]}

Parenti, Anna R. ^{[6
]}

Rosato, Antonio ^{[4
,5
]}

Bicciato, Silvio ^{[7
]}

Balmain, Allan ^{[2
]}

Piccolo, Stefano ^{[1
]}

机构：

[1] Univ Padua, Sch Med, Dept Histol Microbiol & Med Biotechnol, I-35100 Padua, Italy

[2] Univ Calif San Francisco, Canc Res Inst, San Francisco, CA 94115 USA

[3] Univ Padua, Dept Chem Engn Proc, I-35131 Padua, Italy

[4] Univ Padua, Dept Oncol & Surg Sci, I-35126 Padua, Italy

[5] Univ Padua, Ist Oncol Veneto, I-35126 Padua, Italy

[6] Univ Padua, Sect Pathol, Dept Med Diagnost Sci & Special Therapies, I-35126 Padua, Italy

[7] Univ Modena & Reggio Emilia, Dept Biomed Sci, I-41100 Modena, Italy

来源：

CELL | 2009年 / 137卷 / 01期

基金：

瑞士国家科学基金会;

关键词：

LI-FRAUMENI-SYNDROME; BREAST-CANCER; HISTOLOGIC GRADE; MOUSE MODEL; P53; PROGRESSION; MUTANT; GAIN; MICE; P73;

D O I：

10.1016/j.cell.2009.01.039

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

TGF beta ligands act as tumor suppressors in early stage tumors but are paradoxically diverted into potent prometastatic factors in advanced cancers. The molecular nature of this switch remains enigmatic. Here, we show that TGF beta-dependent cell migration, invasion and metastasis are empowered by mutant-p53 and opposed by p63. Mechanistically, TGF beta acts in concert with oncogenic Ras and mutant-p53 to induce the assembly of a mutant-p53/p63 protein complex in which Smads serve as essential platforms. Within this ternary complex, p63 functions are antagonized. Downstream of p63, we identified two candidate metastasis suppressor genes associated with metastasis risk in a large cohort of breast cancer patients. Thus, two common oncogenic lesions, mutant-p53 and Ras, selected in early neoplasms to promote growth and survival, also prefigure a cellular set-up with particular metastasis proclivity by TGF beta-dependent inhibition of p63 function.

引用

页码：87 / 98

页数：12

共 22 条

[1] Metastasis genes: A progression puzzle [J].

Bernards, R ;

Weinberg, RA .

NATURE, 2002, 418 (6900) :823-823

[2] An inducible mouse model for skin cancer reveals distinct roles for gain- and loss-of-function p53 mutations [J].

Caulin, Carlos ;

Nguyen, Thao ;

Lang, Gene A. ;

Goepfert, Thea M. ;

Brinkley, Bill R. ;

Cai, Wei-Wen ;

Lozano, Guillermina ;

Roop, Dennis R. .

JOURNAL OF CLINICAL INVESTIGATION, 2007, 117 (07) :1893-1901

[3] Links between tumor suppressors:: p53 is required for TGF-β gene responses by cooperating with Smads [J].

Cordenonsi, M ;

Dupont, S ;

Maretto, S ;

Insinga, A ;

Imbriano, C ;

Piccolo, S .

CELL, 2003, 113 (03) :301-314

[4] Integration of TGF-β and Ras/MAPK signaling through p53 phosphorylation [J].

Cordenonsi, Michelangelo ;

Montagner, Marco ;

Adorno, Maddalena ;

Zacchigna, Luca ;

Martello, Graziano ;

Mamidi, Anant ;

Soligo, Sandra ;

Dupont, Sirio ;

Piccolo, Stefano .

SCIENCE, 2007, 315 (5813) :840-843

[5] TGF beta 1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice [J].

Cui, W ;

Fowlis, DJ ;

Bryson, S ;

Duffie, E ;

Ireland, H ;

Balmain, A ;

Akhurst, RJ .

CELL, 1996, 86 (04) :531-542

[6] TGF-β signaling in tumor suppression and cancer progression [J].

Derynck, R ;

Akhurst, RJ ;

Balmain, A .

NATURE GENETICS, 2001, 29 (02) :117-129

[7] p63 and p73 in human cancer: defining the network [J].

DeYoung, M. P. ;

Ellisen, L. W. .

ONCOGENE, 2007, 26 (36) :5169-5183

[8] FAM/USP9x, a Deubiquitinating Enzyme Essential for TGFβ Signaling, Controls Smad4 Monoubiquitination [J].

Dupont, Sirio ;

Mamidi, Anant ;

Cordenonsi, Michelangelo ;

Montagner, Marco ;

Zacchigna, Luca ;

Adorno, Maddalena ;

Martello, Graziano ;

Stinchfield, Michael J. ;

Soligo, Sandra ;

Morsut, Leonardo ;

Inui, Masafumi ;

Moro, Stefano ;

Modena, Nicola ;

Argenton, Francesco ;

Newfeld, Stuart J. ;

Piccolo, Stefano .

CELL, 2009, 136 (01) :123-135

[9] Concordance among gene-expression-based predictors for breast cancer [J].

Fan, Cheng ;

Oh, Daniel S. ;

Wessels, Lodewyk ;

Weigelt, Britta ;

Nuyten, Dimitry S. A. ;

Nobel, Andrew B. ;

van't Veer, Laura J. ;

Perou, Charles M. .

NEW ENGLAND JOURNAL OF MEDICINE, 2006, 355 (06) :560-569

[10] Tumor predisposition in mice mutant for p63 and p73:: Evidence for broader tumor suppressor functions for the p53 family [J].

Flores, ER ;

Sengupta, S ;

Miller, JB ;

Newman, JJ ;

Bronson, R ;

Crowley, D ;

Yang, A ;

McKeon, F ;

Jacks, T .

CANCER CELL, 2005, 7 (04) :363-373

← 1 2 3 →