Bi-directional regulation between tyrosine kinase Etk/BMX and tumor suppressor p53 in response to DNA damage

Tianyun Jiang, Zhiyong Guo, Bojie Dai, Miyoung Kang, David K. Ann, Hsing Jien Kung, Yun Qiu

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Etk/Bmx, a member of the Tec family of nonreceptor tyrosine kinases, has been implicated in the regulation of various cellular processes including proliferation, differentiation, motility, and apoptosis. Here, we report the identification of Tec family kinases as the potential interacting proteins of the tumor suppressor p53 by an Src homology 3 domain array screening. Etk is physically associated with p53 through its Src homology 3 domain and the proline-rich domain of p53. Induction of p53 expression by DNA damage inhibits Etk activity in several cell types. Down-regulation of Etk expression by a specific small interfering RNA sensitizes prostate cancer cells to doxorubicin-induced apoptosis, suggesting that inhibition of Etk activity is required for apoptosis in response to DNA damage. We also show that Etk primarily interacts with p53 in the cytoplasm and that such interaction leads to bidirectional inhibition of the activities of both proteins. Overexpression of Etk in prostate cancer cells results in inhibition of p53 transcriptional activity and its interaction with the mitochondrial protein BAK and confers the resistance to doxorubicin. Therefore, we propose that the stoichiometry between p53 and the Tec family kinases in a given cell type may determine its sensitivity to chemotherapeutic drugs.

Original languageEnglish
Pages (from-to)50181-50189
Number of pages9
JournalJournal of Biological Chemistry
Volume279
Issue number48
DOIs
Publication statusPublished - Nov 26 2004
Externally publishedYes

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Protein-Tyrosine Kinases
DNA Damage
Tumors
Apoptosis
Doxorubicin
src Homology Domains
DNA
Phosphotransferases
Cells
Tumor Suppressor Protein p53
Neoplasms
Prostatic Neoplasms
Mitochondrial Proteins
Proline
Stoichiometry
Small Interfering RNA
Screening
Cytoplasm
Down-Regulation
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Biochemistry

Cite this

Bi-directional regulation between tyrosine kinase Etk/BMX and tumor suppressor p53 in response to DNA damage. / Jiang, Tianyun; Guo, Zhiyong; Dai, Bojie; Kang, Miyoung; Ann, David K.; Kung, Hsing Jien; Qiu, Yun.

In: Journal of Biological Chemistry, Vol. 279, No. 48, 26.11.2004, p. 50181-50189.

Research output: Contribution to journalArticle

Jiang, Tianyun ; Guo, Zhiyong ; Dai, Bojie ; Kang, Miyoung ; Ann, David K. ; Kung, Hsing Jien ; Qiu, Yun. / Bi-directional regulation between tyrosine kinase Etk/BMX and tumor suppressor p53 in response to DNA damage. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 48. pp. 50181-50189.
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