Mutant p53 disrupts role of ShcA protein in balancing smad protein-dependent and -independent signaling activity of transforming growth factor-β (TGF-β)

Shu Lin, Lan Yu, Junhua Yang, Zhao Liu, Bijal Karia, Alexander J R Bishop, James Jackson, Guillermina Lozano, John A III Copland, Xiaoxin Mu, Beicheng Sun, Lu Zhe Sun

Research output: Contribution to journalArticle

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Abstract

Biomarkers are lacking for identifying the switch of transforming growth factor-β (TGF-β) from tumor-suppressing to tumor-promoting. Mutated p53 (mp53) has been suggested to switch TGF-β to a tumor promoter. However, we found that mp53 does not always promote the oncogenic role of TGF-β. Here, we show that endogenous mp53 knockdown enhanced cell migration and phosphorylation of ERK in DU145 prostate cancer cells. Furthermore, ectopic expression of mp53 in p53-null PC-3 prostate cancer cells enhanced Smad-dependent signaling but inhibited TGF-β-induced cell migration by downregulating activated ERK. Reactivation of ERK by the expression of its activator, MEK-1, restored TGF-β-induced cell migration. Because TGF-β is known to activate the MAPK/ERK pathway through direct phosphorylation of the adaptor protein ShcA and MAPK/ERK signaling is pivotal to tumor progression, we investigated whether ShcA contributed to mp53-induced ERK inhibition and the conversion of the role of TGF-β during carcinogenesis. We found that mp53 expression led to a decrease of phosphorylated p52ShcA/ERK levels and an increase of phosphorylated Smad levels in a panel of mp53-expressing cancer cell lines and in mammary glands and tumors from mp53 knock-in mice. By manipulating ShcA levels to regulate ERK and Smad signaling in human untransformed and cancer cell lines, we showed that the role of TGF-β in regulating anchoragedependent and -independent growth and migration can be shifted between growth suppression and migration promotion. Thus, our results for the first time suggest that mp53 disrupts the role of ShcA in balancing the Smad-dependent and -independent signaling activity of TGF-β and that ShcA/ERK signaling is a major pathway regulating the tumor-promoting activity of TGF-β.

Original languageEnglish (US)
Pages (from-to)44023-44034
Number of pages12
JournalJournal of Biological Chemistry
Volume286
Issue number51
DOIs
StatePublished - Dec 23 2011

Fingerprint

Smad Proteins
Transforming Growth Factors
Tumors
Proteins
Cells
Cell Movement
Neoplasms
Phosphorylation
Prostatic Neoplasms
Switches
Src Homology 2 Domain-Containing, Transforming Protein 1
Cell Line
MAP Kinase Signaling System
Mitogen-Activated Protein Kinase Kinases
Biomarkers
Human Mammary Glands
Growth
Carcinogens
Carcinogenesis
Down-Regulation

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Mutant p53 disrupts role of ShcA protein in balancing smad protein-dependent and -independent signaling activity of transforming growth factor-β (TGF-β). / Lin, Shu; Yu, Lan; Yang, Junhua; Liu, Zhao; Karia, Bijal; Bishop, Alexander J R; Jackson, James; Lozano, Guillermina; Copland, John A III; Mu, Xiaoxin; Sun, Beicheng; Sun, Lu Zhe.

In: Journal of Biological Chemistry, Vol. 286, No. 51, 23.12.2011, p. 44023-44034.

Research output: Contribution to journalArticle

Lin, Shu ; Yu, Lan ; Yang, Junhua ; Liu, Zhao ; Karia, Bijal ; Bishop, Alexander J R ; Jackson, James ; Lozano, Guillermina ; Copland, John A III ; Mu, Xiaoxin ; Sun, Beicheng ; Sun, Lu Zhe. / Mutant p53 disrupts role of ShcA protein in balancing smad protein-dependent and -independent signaling activity of transforming growth factor-β (TGF-β). In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 51. pp. 44023-44034.
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abstract = "Biomarkers are lacking for identifying the switch of transforming growth factor-β (TGF-β) from tumor-suppressing to tumor-promoting. Mutated p53 (mp53) has been suggested to switch TGF-β to a tumor promoter. However, we found that mp53 does not always promote the oncogenic role of TGF-β. Here, we show that endogenous mp53 knockdown enhanced cell migration and phosphorylation of ERK in DU145 prostate cancer cells. Furthermore, ectopic expression of mp53 in p53-null PC-3 prostate cancer cells enhanced Smad-dependent signaling but inhibited TGF-β-induced cell migration by downregulating activated ERK. Reactivation of ERK by the expression of its activator, MEK-1, restored TGF-β-induced cell migration. Because TGF-β is known to activate the MAPK/ERK pathway through direct phosphorylation of the adaptor protein ShcA and MAPK/ERK signaling is pivotal to tumor progression, we investigated whether ShcA contributed to mp53-induced ERK inhibition and the conversion of the role of TGF-β during carcinogenesis. We found that mp53 expression led to a decrease of phosphorylated p52ShcA/ERK levels and an increase of phosphorylated Smad levels in a panel of mp53-expressing cancer cell lines and in mammary glands and tumors from mp53 knock-in mice. By manipulating ShcA levels to regulate ERK and Smad signaling in human untransformed and cancer cell lines, we showed that the role of TGF-β in regulating anchoragedependent and -independent growth and migration can be shifted between growth suppression and migration promotion. Thus, our results for the first time suggest that mp53 disrupts the role of ShcA in balancing the Smad-dependent and -independent signaling activity of TGF-β and that ShcA/ERK signaling is a major pathway regulating the tumor-promoting activity of TGF-β.",
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AU - Yu, Lan

AU - Yang, Junhua

AU - Liu, Zhao

AU - Karia, Bijal

AU - Bishop, Alexander J R

AU - Jackson, James

AU - Lozano, Guillermina

AU - Copland, John A III

AU - Mu, Xiaoxin

AU - Sun, Beicheng

AU - Sun, Lu Zhe

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AB - Biomarkers are lacking for identifying the switch of transforming growth factor-β (TGF-β) from tumor-suppressing to tumor-promoting. Mutated p53 (mp53) has been suggested to switch TGF-β to a tumor promoter. However, we found that mp53 does not always promote the oncogenic role of TGF-β. Here, we show that endogenous mp53 knockdown enhanced cell migration and phosphorylation of ERK in DU145 prostate cancer cells. Furthermore, ectopic expression of mp53 in p53-null PC-3 prostate cancer cells enhanced Smad-dependent signaling but inhibited TGF-β-induced cell migration by downregulating activated ERK. Reactivation of ERK by the expression of its activator, MEK-1, restored TGF-β-induced cell migration. Because TGF-β is known to activate the MAPK/ERK pathway through direct phosphorylation of the adaptor protein ShcA and MAPK/ERK signaling is pivotal to tumor progression, we investigated whether ShcA contributed to mp53-induced ERK inhibition and the conversion of the role of TGF-β during carcinogenesis. We found that mp53 expression led to a decrease of phosphorylated p52ShcA/ERK levels and an increase of phosphorylated Smad levels in a panel of mp53-expressing cancer cell lines and in mammary glands and tumors from mp53 knock-in mice. By manipulating ShcA levels to regulate ERK and Smad signaling in human untransformed and cancer cell lines, we showed that the role of TGF-β in regulating anchoragedependent and -independent growth and migration can be shifted between growth suppression and migration promotion. Thus, our results for the first time suggest that mp53 disrupts the role of ShcA in balancing the Smad-dependent and -independent signaling activity of TGF-β and that ShcA/ERK signaling is a major pathway regulating the tumor-promoting activity of TGF-β.

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