Differential requirements for Ras and the retinoblastoma tumor suppressor protein in the androgen dependence of prostatic adenocarcinoma cells

Anne F. Fribourg, Karen E. Knudsen, Matthew W. Strobeck, Clint M. Lindhorst, Erik S. Knudsen

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Prostate cells are dependent on androgen for proliferation, but during tumor progression prostate cancer cells achieve independence from the androgen requirement. We report that androgen withdrawal fails to inhibit cell cycle progression or influence the expression of cyclin-dependent kinase (CDK)/cyclins in androgen-independent prostate cancer cells, indicating that these cells signal for cell cycle progression in the absence of androgen. However, phosphorylation of the retinoblastoma tumor suppressor protein (RB) is still required for G1-S progression in androgen-independent cells, since the expression of constitutively active RB (PSM-RB) or p16ink4a caused cell cycle arrest and mimicked the effects of androgen withdrawal on downstream targets in androgen-dependent LNCaP cells. Since Ras is known to mediate mitogenic signaling to RB, we hypothesized that active V12Ras would induce androgen-independent cell cycle progression in LNCaP cells. Although V12Ras was able to stimulate ERK phosphorylation and induce cyclin D1 expression in the absence of androgen, it was not sufficient to promote androgen-independent cell cycle progression. Similarly, ectopic expression of CDK4/cyclin D1, which stimulated RB phosphorylation in the presence of androgen, was incapable of inactivating RB or driving cell cycle progression in the absence of androgen. We show that androgen regulates both CDK4/cyclin D1 and CDK2 complexes to inactivate RB and initiate cell cycle progression. Together, these data show that androgen independence is achieved via deregulation of the androgen to RB signal, and that this signal can only be partially initiated by the Ras pathway in androgen-dependent cells.

Original languageEnglish (US)
Pages (from-to)361-372
Number of pages12
JournalCell Growth and Differentiation
Volume11
Issue number7
StatePublished - Jul 2000

Fingerprint

Tumor Suppressor Proteins
Retinoblastoma Protein
Androgens
Adenocarcinoma
Cell Cycle
Cyclin D1
Phosphorylation
Prostatic Neoplasms
Cyclins
Cyclin-Dependent Kinases

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Differential requirements for Ras and the retinoblastoma tumor suppressor protein in the androgen dependence of prostatic adenocarcinoma cells. / Fribourg, Anne F.; Knudsen, Karen E.; Strobeck, Matthew W.; Lindhorst, Clint M.; Knudsen, Erik S.

In: Cell Growth and Differentiation, Vol. 11, No. 7, 07.2000, p. 361-372.

Research output: Contribution to journalArticle

Fribourg, Anne F. ; Knudsen, Karen E. ; Strobeck, Matthew W. ; Lindhorst, Clint M. ; Knudsen, Erik S. / Differential requirements for Ras and the retinoblastoma tumor suppressor protein in the androgen dependence of prostatic adenocarcinoma cells. In: Cell Growth and Differentiation. 2000 ; Vol. 11, No. 7. pp. 361-372.
@article{6a0be83834894588979f293aabf61ad5,
title = "Differential requirements for Ras and the retinoblastoma tumor suppressor protein in the androgen dependence of prostatic adenocarcinoma cells",
abstract = "Prostate cells are dependent on androgen for proliferation, but during tumor progression prostate cancer cells achieve independence from the androgen requirement. We report that androgen withdrawal fails to inhibit cell cycle progression or influence the expression of cyclin-dependent kinase (CDK)/cyclins in androgen-independent prostate cancer cells, indicating that these cells signal for cell cycle progression in the absence of androgen. However, phosphorylation of the retinoblastoma tumor suppressor protein (RB) is still required for G1-S progression in androgen-independent cells, since the expression of constitutively active RB (PSM-RB) or p16ink4a caused cell cycle arrest and mimicked the effects of androgen withdrawal on downstream targets in androgen-dependent LNCaP cells. Since Ras is known to mediate mitogenic signaling to RB, we hypothesized that active V12Ras would induce androgen-independent cell cycle progression in LNCaP cells. Although V12Ras was able to stimulate ERK phosphorylation and induce cyclin D1 expression in the absence of androgen, it was not sufficient to promote androgen-independent cell cycle progression. Similarly, ectopic expression of CDK4/cyclin D1, which stimulated RB phosphorylation in the presence of androgen, was incapable of inactivating RB or driving cell cycle progression in the absence of androgen. We show that androgen regulates both CDK4/cyclin D1 and CDK2 complexes to inactivate RB and initiate cell cycle progression. Together, these data show that androgen independence is achieved via deregulation of the androgen to RB signal, and that this signal can only be partially initiated by the Ras pathway in androgen-dependent cells.",
author = "Fribourg, {Anne F.} and Knudsen, {Karen E.} and Strobeck, {Matthew W.} and Lindhorst, {Clint M.} and Knudsen, {Erik S.}",
year = "2000",
month = "7",
language = "English (US)",
volume = "11",
pages = "361--372",
journal = "Molecular Cancer Research",
issn = "1541-7786",
publisher = "American Association for Cancer Research Inc.",
number = "7",

}

TY - JOUR

T1 - Differential requirements for Ras and the retinoblastoma tumor suppressor protein in the androgen dependence of prostatic adenocarcinoma cells

AU - Fribourg, Anne F.

AU - Knudsen, Karen E.

AU - Strobeck, Matthew W.

AU - Lindhorst, Clint M.

AU - Knudsen, Erik S.

PY - 2000/7

Y1 - 2000/7

N2 - Prostate cells are dependent on androgen for proliferation, but during tumor progression prostate cancer cells achieve independence from the androgen requirement. We report that androgen withdrawal fails to inhibit cell cycle progression or influence the expression of cyclin-dependent kinase (CDK)/cyclins in androgen-independent prostate cancer cells, indicating that these cells signal for cell cycle progression in the absence of androgen. However, phosphorylation of the retinoblastoma tumor suppressor protein (RB) is still required for G1-S progression in androgen-independent cells, since the expression of constitutively active RB (PSM-RB) or p16ink4a caused cell cycle arrest and mimicked the effects of androgen withdrawal on downstream targets in androgen-dependent LNCaP cells. Since Ras is known to mediate mitogenic signaling to RB, we hypothesized that active V12Ras would induce androgen-independent cell cycle progression in LNCaP cells. Although V12Ras was able to stimulate ERK phosphorylation and induce cyclin D1 expression in the absence of androgen, it was not sufficient to promote androgen-independent cell cycle progression. Similarly, ectopic expression of CDK4/cyclin D1, which stimulated RB phosphorylation in the presence of androgen, was incapable of inactivating RB or driving cell cycle progression in the absence of androgen. We show that androgen regulates both CDK4/cyclin D1 and CDK2 complexes to inactivate RB and initiate cell cycle progression. Together, these data show that androgen independence is achieved via deregulation of the androgen to RB signal, and that this signal can only be partially initiated by the Ras pathway in androgen-dependent cells.

AB - Prostate cells are dependent on androgen for proliferation, but during tumor progression prostate cancer cells achieve independence from the androgen requirement. We report that androgen withdrawal fails to inhibit cell cycle progression or influence the expression of cyclin-dependent kinase (CDK)/cyclins in androgen-independent prostate cancer cells, indicating that these cells signal for cell cycle progression in the absence of androgen. However, phosphorylation of the retinoblastoma tumor suppressor protein (RB) is still required for G1-S progression in androgen-independent cells, since the expression of constitutively active RB (PSM-RB) or p16ink4a caused cell cycle arrest and mimicked the effects of androgen withdrawal on downstream targets in androgen-dependent LNCaP cells. Since Ras is known to mediate mitogenic signaling to RB, we hypothesized that active V12Ras would induce androgen-independent cell cycle progression in LNCaP cells. Although V12Ras was able to stimulate ERK phosphorylation and induce cyclin D1 expression in the absence of androgen, it was not sufficient to promote androgen-independent cell cycle progression. Similarly, ectopic expression of CDK4/cyclin D1, which stimulated RB phosphorylation in the presence of androgen, was incapable of inactivating RB or driving cell cycle progression in the absence of androgen. We show that androgen regulates both CDK4/cyclin D1 and CDK2 complexes to inactivate RB and initiate cell cycle progression. Together, these data show that androgen independence is achieved via deregulation of the androgen to RB signal, and that this signal can only be partially initiated by the Ras pathway in androgen-dependent cells.

UR - http://www.scopus.com/inward/record.url?scp=0033865682&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033865682&partnerID=8YFLogxK

M3 - Article

VL - 11

SP - 361

EP - 372

JO - Molecular Cancer Research

JF - Molecular Cancer Research

SN - 1541-7786

IS - 7

ER -