p53 and its mutants in tumor cell migration and invasion

In about half of all human cancers, the tumor suppressor p53 protein is either lost or mutated, frequently resulting in the expression of a transcriptionally inactive mutant p53 protein. Loss of p53 function is well known to influence cell cycle checkpoint controls and apoptosis. But it is now clear that p53 regulates other key stages of metastatic progression, such as cell migration and invasion. Moreover, recent data suggests that expression of mutant p53 is not the equivalent of p53 loss, and that mutant p53s can acquire new functions to drive cell migration, invasion, and metastasis, in part by interfering with p63 function.

[1]  Julie A. Wilkins,et al.  p53 mutation and loss have different effects on tumourigenesis in a novel mouse model of pleomorphic rhabdomyosarcoma , 2010, The Journal of pathology.

[2]  Christopher W. Wong,et al.  RCP is a human breast cancer-promoting gene with Ras-activating function. , 2009, The Journal of clinical investigation.

[3]  Lakshmanane Boominathan The Tumor Suppressors p53, p63, and p73 Are Regulators of MicroRNA Processing Complex , 2010, PloS one.

[4]  Ker-Chau Li,et al.  p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug , 2009, Nature Cell Biology.

[5]  H. Izumi,et al.  Twist and p53 reciprocally regulate target genes via direct interaction , 2008, Oncogene.

[6]  M. Oren,et al.  Physical Interaction with Human Tumor-derived p53 Mutants Inhibits p63 Activities* , 2002, The Journal of Biological Chemistry.

[7]  E. Sahai,et al.  Imaging amoeboid cancer cell motility in vivo , 2008, Journal of microscopy.

[8]  Anne J. Ridley,et al.  Mammalian Rho GTPases: new insights into their functions from in vivo studies , 2008, Nature Reviews Molecular Cell Biology.

[9]  S. Jakowlew Transforming growth factor-β in cancer and metastasis , 2006, Cancer and Metastasis Reviews.

[10]  H. Kotani,et al.  Mutant p53 induces the GEF-H1 oncogene, a guanine nucleotide exchange factor-H1 for RhoA, resulting in accelerated cell proliferation in tumor cells. , 2006, Cancer research.

[11]  C. Prives,et al.  p73 Function Is Inhibited by Tumor-Derived p53 Mutants in Mammalian Cells , 1999, Molecular and Cellular Biology.

[12]  Victoria Sanz-Moreno,et al.  Rho-GTPase signaling drives melanoma cell plasticity , 2009, Cell cycle.

[13]  Christopher E Barbieri,et al.  Loss of p63 leads to increased cell migration and up-regulation of genes involved in invasion and metastasis. , 2006, Cancer research.

[14]  Keara M. Lane,et al.  Dicer1 functions as a haploinsufficient tumor suppressor. , 2009, Genes & development.

[15]  S. Hsue,et al.  Expression of p63 (TA and deltaN isoforms) in human primary well differentiated buccal carcinomas. , 2004, International journal of oral and maxillofacial surgery.

[16]  M. Fraga,et al.  The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors , 2003, Journal of Cell Science.

[17]  T. Jacks,et al.  Mutant p53 Gain of Function in Two Mouse Models of Li-Fraumeni Syndrome , 2004, Cell.

[18]  H. Horvitz,et al.  MicroRNA expression profiles classify human cancers , 2005, Nature.

[19]  A. Ridley,et al.  Inhibition of ROCK by RhoE. , 2006, Methods in enzymology.

[20]  T. Jacks,et al.  The role of p53 in tumour suppression: lessons from mouse models , 1999, Cellular and Molecular Life Sciences CMLS.

[21]  S. Nomoto,et al.  ΔNp63α and TAp63α regulate transcription of genes with distinct biological functions in cancer and development , 2003 .

[22]  G. Hannon,et al.  The miRNA-Processing Enzyme Dicer Is Essential for the Morphogenesis and Maintenance of Hair Follicles , 2006, Current Biology.

[23]  Stephen N. Jones,et al.  Regulation of p53 stability by Mdm2 , 1997, Nature.

[24]  Hartmut Land,et al.  Tumor suppressor p53 restricts Ras stimulation of RhoA and cancer cell motility , 2007, Nature Structural &Molecular Biology.

[25]  R. Knight,et al.  TAp63 and ΔNp63 in Cancer and Epidermal Development , 2007 .

[26]  G. Bossi,et al.  Mutant p53-induced Up-regulation of Mitogen-activated Protein Kinase Kinase 3 Contributes to Gain of Function* , 2010, The Journal of Biological Chemistry.

[27]  V. Rotter,et al.  Mutant p53 gain-of-function in cancer. , 2010, Cold Spring Harbor perspectives in biology.

[28]  R. Knight,et al.  TAp63 and DeltaNp63 in cancer and epidermal development. , 2007, Cell cycle.

[29]  O. Renner,et al.  Exploring the Gain of Function Contribution of AKT to Mammary Tumorigenesis in Mouse Models , 2010, PloS one.

[30]  T. Mak,et al.  Regulation of PTEN transcription by p53. , 2001, Molecular cell.

[31]  K. Kihara,et al.  Impaired p63 expression associates with poor prognosis and uroplakin III expression in invasive urothelial carcinoma of the bladder. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[32]  Jeremy J. W. Chen,et al.  Transcription Repressor Slug Promotes Carcinoma Invasion and Predicts Outcome of Patients with Lung Adenocarcinoma , 2005, Clinical Cancer Research.

[33]  I. Wistuba,et al.  TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs , 2010, Nature.

[34]  Yi Zheng,et al.  p19Arf-p53 Tumor Suppressor Pathway Regulates Cell Motility by Suppression of Phosphoinositide 3-Kinase and Rac1 GTPase Activities* , 2003, The Journal of Biological Chemistry.

[35]  P. Chumakov,et al.  Tumor suppressor p53 and its homologue p73alpha affect cell migration. , 2003, The Journal of biological chemistry.

[36]  E. Manser,et al.  The RhoA GEF Syx Is a Target of Rnd3 and Regulated via a Raf1-Like Ubiquitin-Related Domain , 2010, PloS one.

[37]  N. Voirin,et al.  Prognostic value of Dicer expression in human breast cancers and association with the mesenchymal phenotype , 2009, British Journal of Cancer.

[38]  R. Eves,et al.  p53 Suppresses Src-Induced Podosome and Rosette Formation and Cellular Invasiveness through the Upregulation of Caldesmon , 2009, Molecular and Cellular Biology.

[39]  S. Chi,et al.  Frequent alteration of p63 expression in human primary bladder carcinomas. , 2000, Cancer research.

[40]  J. Settleman,et al.  Rnd Proteins Function as RhoA Antagonists by Activating p190 RhoGAP , 2003, Current Biology.

[41]  Sarah A. Boswell,et al.  RETRACTED: RhoE Is a Pro-Survival p53 Target Gene that Inhibits ROCK I-Mediated Apoptosis in Response to Genotoxic Stress , 2006, Current Biology.

[42]  S. Lowe,et al.  TAp63 induces senescence and suppresses tumorigenesis in vivo , 2009, Nature Cell Biology.

[43]  C. Prives,et al.  Are interactions with p63 and p73 involved in mutant p53 gain of oncogenic function? , 2007, Oncogene.

[44]  V. Rotter,et al.  Conditional RNA interference in vivo to study mutant p53 oncogenic gain of function on tumor malignancy , 2008, Cell cycle.

[45]  D. Peeper,et al.  Deregulating EMT and senescence: double impact by a single twist. , 2008, Cancer cell.

[46]  J. Norman,et al.  Integrins: masters and slaves of endocytic transport , 2009, Nature Reviews Molecular Cell Biology.

[47]  S. Jakowlew Transforming growth factor-beta in cancer and metastasis. , 2006, Cancer metastasis reviews.

[48]  P. Coates,et al.  p63 contributes to cell invasion and migration in squamous cell carcinoma of the head and neck. , 2008, Cancer letters.

[49]  C. Prives,et al.  A Subset of Tumor-Derived Mutant Forms of p53 Down-Regulate p63 and p73 through a Direct Interaction with the p53 Core Domain , 2001, Molecular and Cellular Biology.

[50]  J. Garlick,et al.  Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCKalpha kinases. , 2007, Genes & development.

[51]  W. Deppert,et al.  Mutant p53R270H gain of function phenotype in a mouse model for oncogene‐induced mammary carcinogenesis , 2007, International journal of cancer.

[52]  A. Lenferink,et al.  Differential endocytic routing of homo‐ and hetero‐dimeric ErbB tyrosine kinases confers signaling superiority to receptor heterodimers , 1998, The EMBO journal.

[53]  You-ji Feng,et al.  Elevated expression of p53 gain-of-function mutation R175H in endometrial cancer cells can increase the invasive phenotypes by activation of the EGFR/PI3K/AKT pathway , 2009, Molecular Cancer.

[54]  G. Condorelli,et al.  MicroRNA control of podosome formation in vascular smooth muscle cells in vivo and in vitro , 2010, The Journal of cell biology.

[55]  V. Rotter,et al.  Mutant p53 Attenuates the SMAD-Dependent Transforming Growth Factor β1 (TGF-β1) Signaling Pathway by Repressing the Expression of TGF-β Receptor Type II , 2007, Molecular and Cellular Biology.

[56]  B. Li,et al.  neu/ERBB2 cooperates with p53-172H during mammary tumorigenesis in transgenic mice , 1997, Molecular and cellular biology.

[57]  M. Mayo,et al.  Gain of oncogenic function of p53 mutants induces invasive phenotypes in human breast cancer cells by silencing CCN5/WISP-2. , 2008, Cancer research.

[58]  Pierre Roux,et al.  Control of cell migration: a tumour suppressor function for p53? , 2006, Biology of the cell.

[59]  D. Notterman,et al.  Analysis of p53-regulated gene expression patterns using oligonucleotide arrays. , 2000, Genes & development.

[60]  Yi Zheng,et al.  Rho family GTPases cooperate with p53 deletion to promote primary mouse embryonic fibroblast cell invasion , 2004, Oncogene.

[61]  J. Vandesompele,et al.  Monoallelic but not biallelic loss of Dicer1 promotes tumorigenesis in vivo , 2010, Cell Death and Differentiation.

[62]  Paul Timpson,et al.  Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer , 2010, Proceedings of the National Academy of Sciences.

[63]  V. Rotter,et al.  Repression of the MSP/MST-1 gene contributes to the antiapoptotic gain of function of mutant p53 , 2006, Oncogene.

[64]  Pierre Roux,et al.  Loss of p53 promotes RhoA–ROCK-dependent cell migration and invasion in 3D matrices , 2007, The Journal of cell biology.

[65]  P. Jeffrey,et al.  Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. , 1994, Science.

[66]  Bei Wang,et al.  LIM and SH3 protein 1 (Lasp1) is a novel p53 transcriptional target involved in hepatocellular carcinoma. , 2009, Journal of hepatology.

[67]  V. Rotter,et al.  Mutant p53R175H upregulates Twist1 expression and promotes epithelial–mesenchymal transition in immortalized prostate cells , 2011, Cell Death and Differentiation.

[68]  A. Levine,et al.  Two critical hydrophobic amino acids in the N-terminal domain of the p53 protein are required for the gain of function phenotypes of human p53 mutants. , 1995, Oncogene.

[69]  P. Roux,et al.  Regulation of Cdc42‐mediated morphological effects: a novel function for p53 , 2002, The EMBO journal.

[70]  F. Ferrari,et al.  A MicroRNA Targeting Dicer for Metastasis Control , 2010, Cell.

[71]  Y. Soini,et al.  A mutant TP53 gene status is associated with a poor prognosis and anthracycline-resistance in breast cancer patients. , 2003, European journal of cancer.

[72]  J. Norman,et al.  Mutant p53 Drives Invasion by Promoting Integrin Recycling , 2009, Cell.

[73]  Jesse D. Martinez,et al.  Different mutant/wild-type p53 combinations cause a spectrum of increased invasive potential in nonmalignant immortalized human mammary epithelial cells. , 2008, Neoplasia.

[74]  L. Strong,et al.  Gain of Function of a p53 Hot Spot Mutation in a Mouse Model of Li-Fraumeni Syndrome , 2004, Cell.

[75]  C. Cordon-Cardo,et al.  Loss of p63 expression is associated with tumor progression in bladder cancer. , 2002, The American journal of pathology.

[76]  V. Rotter,et al.  Integrity of the N‐terminal transcription domain of p53 is required for mutant p53 interference with drug‐induced apoptosis , 2001, The EMBO journal.

[77]  V. Rotter,et al.  Mutant p53 attenuates the SMAD-dependent transforming growth factor beta1 (TGF-beta1) signaling pathway by repressing the expression of TGF-beta receptor type II. , 2007, Molecular and cellular biology.

[78]  B. Kennedy,et al.  NPAT links cyclin E-Cdk2 to the regulation of replication-dependent histone gene transcription. , 2000, Genes & development.

[79]  P. Chumakov,et al.  Tumor Suppressor p53 and Its Homologue p73α Affect Cell Migration* , 2003, Journal of Biological Chemistry.

[80]  M. Baudry,et al.  A Novel Function for p53: Regulation of Growth Cone Motility through Interaction with Rho Kinase , 2009, The Journal of Neuroscience.

[81]  I. Simon,et al.  Modulation of the vitamin D3 response by cancer-associated mutant p53. , 2010, Cancer cell.

[82]  M. Oren,et al.  Mdm2 promotes the rapid degradation of p53 , 1997, Nature.

[83]  Andrew J. Lindsay,et al.  Rab-coupling protein coordinates recycling of α5β1 integrin and EGFR1 to promote cell migration in 3D microenvironments , 2008, The Journal of cell biology.

[84]  A. Yang,et al.  Tumor predisposition in mice mutant for p63 and p73: evidence for broader tumor suppressor functions for the p53 family. , 2005, Cancer cell.

[85]  Margaret Ashcroft,et al.  Regulation of p53 stability , 1999, Oncogene.

[86]  Hyojin Cho,et al.  Many new down‐ and up‐regulatory signaling pathways, from known cancer progression suppressors to matrix metalloproteinases, differ widely in cells of various cancers , 2010, Journal of cellular physiology.

[87]  Misako Sato,et al.  P63 expression in normal, hyperplastic and malignant breast tissues , 2002, Breast cancer.

[88]  V. Rotter,et al.  Mutant p53 protein expression interferes with p53-independent apoptotic pathways , 1998, Oncogene.

[89]  Erik Sahai,et al.  Differing modes of tumour cell invasion have distinct requirements for Rho/ROCK signalling and extracellular proteolysis , 2003, Nature Cell Biology.

[90]  C. Kang,et al.  Downregulation of Dicer enhances tumor cell proliferation and invasion. , 2010, International journal of oncology.

[91]  V. Rotter,et al.  Transactivation of the EGR1 Gene Contributes to Mutant p53 Gain of Function , 2004, Cancer Research.

[92]  A. Hall,et al.  Rho GTPases and their effector proteins. , 2000, The Biochemical journal.

[93]  M. Kapoor,et al.  High metastatic potential in mice inheriting a targeted p53 missense mutation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[94]  M. Sarbia,et al.  Slug is overexpressed in gastric carcinomas and may act synergistically with SIP1 and Snail in the down‐regulation of E‐cadherin , 2007, The Journal of pathology.

[95]  T. Fleming,et al.  Transcriptional repression of epithelial cell adhesion molecule contributes to p53 control of breast cancer invasion. , 2009, Cancer research.

[96]  Jos Jonkers,et al.  Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis. , 2006, Cancer cell.

[97]  A. Balmain,et al.  Expression pattern of the cell adhesion molecules. E-cadherin, P-cadherin and alpha 6 beta 4 intergrin is altered in pre-malignant skin tumors of p53-deficient mice. , 1996, International journal of cancer.

[98]  Antonio Rosato,et al.  A Mutant-p53/Smad Complex Opposes p63 to Empower TGFβ-Induced Metastasis , 2009, Cell.

[99]  A. Balmain,et al.  Expression pattern of the cell adhesion molecules E‐cadherin, P‐cadherin and α6β4 integrin is altered in pre‐malignant skin tumors of p53‐deficient mice , 1996 .

[100]  S. Nomoto,et al.  DeltaNp63alpha and TAp63alpha regulate transcription of genes with distinct biological functions in cancer and development. , 2003, Cancer research.

[101]  M. Hollstein,et al.  p53 gain-of-function cancer mutants induce genetic instability by inactivating ATM , 2007, Nature Cell Biology.

[102]  Y. Xu,et al.  A common gain of function of p53 cancer mutants in inducing genetic instability , 2010, Oncogene.

[103]  Jason S. Carroll,et al.  p63 regulates an adhesion programme and cell survival in epithelial cells , 2006, Nature Cell Biology.

[104]  V. Rotter,et al.  Mutant p53 facilitates somatic cell reprogramming and augments the malignant potential of reprogrammed cells , 2010, The Journal of experimental medicine.

[105]  J. Vasiliev,et al.  Changes in p53 expression in mouse fibroblasts can modify motility and extracellular matrix organization , 2000, Oncogene.

[106]  A. Levine,et al.  Physical and Functional Interaction between p53 Mutants and Different Isoforms of p73* , 2000, The Journal of Biological Chemistry.