E2F Activity Is Biphasically Regulated by Androgens in LNCaP Cells

Hofman, Kurt; Swinnen, Johannes V.; Verhoeven, Guido; Heyns, Walter

doi:10.1006/bbrc.2001.4738

Cited by 52 publications

(39 citation statements)

References 24 publications

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“…Many of these genes are involved in cell cycle progression and DNA replication (Flemington et al 1993, Helin et al 1993, Weintraub et al 1995, La Thangue 1996, Dyson 1998, Harbour & Dean 2000. As we could previously show in LNCaP cells (Hofman et al 2001) the regulation of cell proliferation by androgens is accompanied by major changes in E2F activity. Most probably these changes are largely due to androgen-dependent changes in the phosphorylation state of Rb, mediated in turn by the activity of cyclindependent kinases and their inhibitors.…”

Section: Discussionmentioning

confidence: 65%

The retinoblastoma protein-associated transcription repressor RBaK interacts with the androgen receptor and enhances its transcriptional activity

Hofman

Swinnen²,

Claessens³

et al. 2003

Journal of Molecular Endocrinology

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In search of potential androgen receptor coregulators we performed a yeast two-hybrid screening using the androgen receptor ligand-binding domain as bait and a human prostate cDNA library as prey and found that the carboxy-terminal domain of retinoblastoma-associated Krüppel protein (RbaK), a member of the Krüppel zinc finger protein family, interacts in a ligand-dependent way with the ligand-binding domain of the androgen receptor. RBaK was recently identified as a transcriptional regulator that interacts with the retinoblastoma protein and thereby influences E2F regulated transcription. The interaction of RBaK with the androgen receptor was further documented using mammalian two-hybrid experiments, in vitro binding studies and coimmunoprecipitation. Finally, we demonstrated that both RBaK and the retinoblastoma protein coactivate androgen receptor-mediated transcription in cotransfection experiments. In conclusion, our data show that RBaK interacts with the androgen receptor and increases its transcriptional activity. Moreover, the double interaction of RBaK with the retinoblastoma protein and with the androgen receptor provides a novel link between the androgen receptor and the regulation of the cell cycle.

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Section: Discussionmentioning

confidence: 65%

The retinoblastoma protein-associated transcription repressor RBaK interacts with the androgen receptor and enhances its transcriptional activity

Hofman

Swinnen²,

Claessens³

et al. 2003

Journal of Molecular Endocrinology

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“…Low concentrations (up to 0.1 nM) of androgen stimulate cell proliferation, whereas high concentrations (higher than 1 nM) of androgen result in strong inhibition of proliferation and increase the expression of PSA and other differentiation markers (Henttu et al, 1992;Esquenet et al, 1996;Knudsen et al, 1998;Tsihlias et al, 2000). Studies have shown that the effect of androgen on LNCaP cell proliferation is closely reflected in the degree of Rb phosphorylation and in the level of E2F activity (Hofman et al, 2001). At androgen concentrations up to 0.1 nM, E2F activity increases in parallel with Rb phosphorylation, and a similar stimulation of E2F target genes, cyclin A and E2F-1, is observed.…”

Section: Discussionmentioning

confidence: 99%

Androgen signaling is required for the vitamin D-mediated growth inhibition in human prostate cancer cells

Bao

Ting

et al. 2004

Oncogene

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Epidemiological data on prostate cancer incidence has suggested that vitamin D deficiency may be a risk factor for prostate cancer. The antiproliferative activity of 1a, 25-dihydroxyvitamin D 3 (1,25-VD) and its analogues has been demonstrated in many prostate cancer models, yet the detailed mechanisms underlying this protective effect of vitamin D remain to be determined. Here, we demonstrate that two androgen receptor (AR)-positive prostate cancer cell lines, LNCaP and CWR22R, are more sensitive to the growth inhibitory effects of 1,25-VD compared to the AR-negative prostate cancer cell lines, PC-3 and DU 145. 1,25-VD treatment inhibited cyclindependent kinase 2 (cdk2) activity and induced G0/G1 arrest. Interestingly, we also found that 1,25-VD treatment induced the expression of AR, and that the onset of the G0/G1 arrest in LNCaP and CWR22R cells is correlated with the onset of increasing expression of AR. This implies that the antiproliferative actions of 1,25-VD in AR-positive prostate cancer might be mediated through AR. Furthermore, a reduction in 1,25-VD-mediated growth inhibition was observed when AR signaling was blocked by antiandrogens, AR RNA interference, or targeted disruption of AR. Taken together, our data suggest that the androgen/AR signaling plays an important role in the antiproliferative effects of 1,25-VD and restoration of androgen responsiveness by 1,25-VD might be beneficial for the treatment of hormone-refractory prostate cancer patients.

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“…Plasmids-A TK-TATA luciferase reporter vector served as a control vector for the same reporter construct in which six artificial E2F binding sites were cloned (20). The pGL3-Basic reporter vector (Promega, Madison, WI) was used as control for pGL3-Basic vectors in which both short and long fragments of the intergenic regions of mouse Melk and Cnap1 were cloned.…”

Section: Methodsmentioning

confidence: 99%

Characterization of the Condensin Component Cnap1 and Protein Kinase Melk as Novel E2F Target Genes Down-regulated by 1,25-Dihydroxyvitamin D3

Verlinden

Eelen

Beullens

et al. 2005

Journal of Biological Chemistry

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Active complexes between cyclin D and cyclin-dependent kinases 4/6 regulate the transition through the G 1 /S restriction point by phosphorylation of the retinoblastoma protein (pRb) 3 and other members of the pocket protein family, p107 and p130. The phosphorylation status of these pocket proteins determines their association with members of the E2F family of transcriptional regulators, which play a pivotal role in mediating gene expression during cell proliferation. These E2F proteins can be allocated to four subclasses. Upon release by their pocket protein pRb, E2Fs 1-3 function as transcriptional activators in late G 1 and in S phase. E2F4 and E2F5 act as transcriptional repressors in quiescent and early G 1 cells by associating with p107 or p130 (1, 2). In quiescent cells repression of the promoter activity of E2F target genes is associated with the recruitment of E2F4 and p130 and low levels of histone acetylation. By late G 1 , these proteins are largely replaced by activator E2Fs in concert with histone acetylation and gene activation. It is, therefore, likely that two pathways, one controlled by pRb and the other by p130/p107, regulate distinct downstream events required for G 1 progression and G 1 /S transition (2, 3). Recently, the transcriptional repressor E2F6 was proposed to make up the third subclass of E2F proteins (4, 5), whereas E2F7 and E2F8 form the last subclass and are thought to regulate a subset of E2F target genes during the cell cycle (6, 7).1,25-Dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), the active metabolite of vitamin D 3 , acts on bone and mineral homeostasis and also inhibits proliferation and induces differentiation of various normal and malignant cells (8). However, the exact molecular mechanism behind this growth-inhibitory effect is unknown. 1,25(OH) 2 D 3 has a cell cycle-specific effect leading to an accumulation of cells in the G 1 phase of the cell cycle (9). It has been shown previously that 1,25(OH) 2 D 3 reduces the activity of the cyclin D1-cyclin-dependent kinase 4/6 complex, which may contribute to its antiproliferative effect (10).In the present study a cDNA microarray was performed to examine the expression profile of 21,492 genes in MC3T3-E1 cells treated with 1,25(OH) 2 D 3 for different times up to 36 h. Statistical analysis revealed a cluster of down-regulated genes involved in cell cycle regulation and in DNA replication but also in checkpoint control, DNA repair, chromosome transactions, and mitosis. Approximately 30% of the genes in this cluster are known E2F targets, and in silico promoter analysis demonstrated an additional 20% of the genes to contain E2F binding sites in their promoter. Four of these genes were selected for further analysis, namely Cnap1, Melk, retroviral integration site 2 (Ris2), and enhancer of Zeste homolog 2 (Ezh2). Expression of these genes was growth-regulated as were the promoter activities of Cnap1 and Melk. Mutational analysis revealed that the identified E2F binding sites were required for transactivation by E2F family members. R...

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E2F Activity Is Biphasically Regulated by Androgens in LNCaP Cells

Cited by 52 publications

References 24 publications

The retinoblastoma protein-associated transcription repressor RBaK interacts with the androgen receptor and enhances its transcriptional activity

The retinoblastoma protein-associated transcription repressor RBaK interacts with the androgen receptor and enhances its transcriptional activity

Androgen signaling is required for the vitamin D-mediated growth inhibition in human prostate cancer cells

Characterization of the Condensin Component Cnap1 and Protein Kinase Melk as Novel E2F Target Genes Down-regulated by 1,25-Dihydroxyvitamin D3

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