Androgens repress expression of the f-box protein Skp2 via p107 dependent and independent mechanisms in LNCaP prostate cancer cells

Jingting Jiang, Yunqian Pan, Kevin M. Regan, Changping Wu, Xueguang Zhang, Donald J. Tindall, Haojie Huang

Research output: Contribution to journalArticle

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Abstract

BACKGROUND Androgens control homeostasis of the normal prostate and growth of prostate cancer (PCa) through the androgen receptor (AR) by regulating gene networks involving in cell proliferation, differentiation, and survival. We demonstrated previously that expression of Skp2, a key protein regulating cell entry into the S phase, is inhibited by androgens in an AR-dependent manner (Oncogene, 2004; 23(12): 2161-2176). However, the underlying mechanism of this regulation is unknown. METHODS Using the LNCaP PCa cell line as a working model, the effect of androgens on the expression of Skp2 was examined by Western and Northern blot analyses. Cell cycle was measured by fluorescence-activated cell sorting (FACS). Gene transfection was performed by electroporation to manipulate the expression levels of proteins studied. RESULTS At physiological levels androgens markedly repressed Skp2 expression but slightly induced Skp2 expression at subphysiological levels. Androgens modestly decreased the stability of the Skp2 protein. Androgenic repression of Skp2 expression was completely abolished by E1A-mediated inactivation of pocket proteins including RB, p130, and p107. Moreover, ectopic expression of p107 inhibited Skp2 expression, and silencing of p107 partially blocked androgenic repression of Skp2. CONCLUSIONS Our data indicate that androgens repress Skp2 expression via p107-dependent and -independent pathways in PCa cells. These regulatory mechanisms may be targeted for the development of new therapeutics of androgen-refractory PCa. Prostate 72:225-232, 2012.

Original languageEnglish (US)
Pages (from-to)225-232
Number of pages8
JournalProstate
Volume72
Issue number2
DOIs
StatePublished - Feb 1 2012

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S-Phase Kinase-Associated Proteins
Androgens
Prostatic Neoplasms
Androgen Receptors
Proteins
Electroporation
Gene Regulatory Networks
S Phase
Oncogenes
Northern Blotting
Transfection
Prostate
Cell Differentiation
Cell Survival
Cell Cycle
Flow Cytometry
Homeostasis
Western Blotting
Cell Proliferation
Cell Line

Keywords

  • androgen
  • p107
  • Skp2

ASJC Scopus subject areas

  • Urology
  • Oncology

Cite this

Androgens repress expression of the f-box protein Skp2 via p107 dependent and independent mechanisms in LNCaP prostate cancer cells. / Jiang, Jingting; Pan, Yunqian; Regan, Kevin M.; Wu, Changping; Zhang, Xueguang; Tindall, Donald J.; Huang, Haojie.

In: Prostate, Vol. 72, No. 2, 01.02.2012, p. 225-232.

Research output: Contribution to journalArticle

Jiang, Jingting ; Pan, Yunqian ; Regan, Kevin M. ; Wu, Changping ; Zhang, Xueguang ; Tindall, Donald J. ; Huang, Haojie. / Androgens repress expression of the f-box protein Skp2 via p107 dependent and independent mechanisms in LNCaP prostate cancer cells. In: Prostate. 2012 ; Vol. 72, No. 2. pp. 225-232.
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AU - Pan, Yunqian

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AU - Wu, Changping

AU - Zhang, Xueguang

AU - Tindall, Donald J.

AU - Huang, Haojie

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N2 - BACKGROUND Androgens control homeostasis of the normal prostate and growth of prostate cancer (PCa) through the androgen receptor (AR) by regulating gene networks involving in cell proliferation, differentiation, and survival. We demonstrated previously that expression of Skp2, a key protein regulating cell entry into the S phase, is inhibited by androgens in an AR-dependent manner (Oncogene, 2004; 23(12): 2161-2176). However, the underlying mechanism of this regulation is unknown. METHODS Using the LNCaP PCa cell line as a working model, the effect of androgens on the expression of Skp2 was examined by Western and Northern blot analyses. Cell cycle was measured by fluorescence-activated cell sorting (FACS). Gene transfection was performed by electroporation to manipulate the expression levels of proteins studied. RESULTS At physiological levels androgens markedly repressed Skp2 expression but slightly induced Skp2 expression at subphysiological levels. Androgens modestly decreased the stability of the Skp2 protein. Androgenic repression of Skp2 expression was completely abolished by E1A-mediated inactivation of pocket proteins including RB, p130, and p107. Moreover, ectopic expression of p107 inhibited Skp2 expression, and silencing of p107 partially blocked androgenic repression of Skp2. CONCLUSIONS Our data indicate that androgens repress Skp2 expression via p107-dependent and -independent pathways in PCa cells. These regulatory mechanisms may be targeted for the development of new therapeutics of androgen-refractory PCa. Prostate 72:225-232, 2012.

AB - BACKGROUND Androgens control homeostasis of the normal prostate and growth of prostate cancer (PCa) through the androgen receptor (AR) by regulating gene networks involving in cell proliferation, differentiation, and survival. We demonstrated previously that expression of Skp2, a key protein regulating cell entry into the S phase, is inhibited by androgens in an AR-dependent manner (Oncogene, 2004; 23(12): 2161-2176). However, the underlying mechanism of this regulation is unknown. METHODS Using the LNCaP PCa cell line as a working model, the effect of androgens on the expression of Skp2 was examined by Western and Northern blot analyses. Cell cycle was measured by fluorescence-activated cell sorting (FACS). Gene transfection was performed by electroporation to manipulate the expression levels of proteins studied. RESULTS At physiological levels androgens markedly repressed Skp2 expression but slightly induced Skp2 expression at subphysiological levels. Androgens modestly decreased the stability of the Skp2 protein. Androgenic repression of Skp2 expression was completely abolished by E1A-mediated inactivation of pocket proteins including RB, p130, and p107. Moreover, ectopic expression of p107 inhibited Skp2 expression, and silencing of p107 partially blocked androgenic repression of Skp2. CONCLUSIONS Our data indicate that androgens repress Skp2 expression via p107-dependent and -independent pathways in PCa cells. These regulatory mechanisms may be targeted for the development of new therapeutics of androgen-refractory PCa. Prostate 72:225-232, 2012.

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