Restoration of retinoblastoma mediated signaling to Cdk2 results in cell cycle arrest

Strobeck, Matthew W.; Fribourg, Anne F.; Puga, Alvaro; Knudsen, Erik S.

doi:10.1038/sj.onc.1203510

Cited by 69 publications

(54 citation statements)

References 51 publications

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“…Consistent with these observations, livers from AHR knockout mice showed increased levels of TGF-β1 and TGF-β3 proteins and elevated numbers of hepatocytes undergoing apoptosis compared to wild-type mice (Zaher et al, 1998). Second, protein interactions between AHR and RB further repress the RB-dependent repression of the transcription factor E2F and prevent entry of the cells into S-phase (Ge and Elferink, 1998;Puga et al, 2000;Strobeck et al, 2000;Marlowe et al, 2004). Hence, under certain circumstances the AHR could be considered as a pro-proliferative gene with the properties of an oncogene, and under others as a tumor suppressor gene.…”

Section: Introductionsupporting

confidence: 63%

“…The AHR has also been recognized as a cell cycle regulator (Ma and Whitlock, 1996;Weiss et al, 1996;Ge and Elferink, 1998;Kolluri et al, 1999;Puga et al, 2000;Strobeck et al, 2000;Marlowe et al, 2004) although the precise molecular mechanisms responsible for this role have not been fully elucidated. In the absence of an exogenous ligand, or after deletion of the ligand-binding PAS-B domain, the AHR has been shown to promote cell cycle progression (Ma and Whitlock, 1996;Elizondo et al, 2000;Chang et al, 2007), whereas exposure to its prototypical ligand, TCDD, inhibits cell cycle proliferation in an AHR-dependent manner (Bauman et al, 1995;Hushka and Greenlee, 1995;Levine-Fridman, Chen, and Elferink, 2004;Marlowe et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Repression of Ah receptor and induction of transforming growth factor-β genes in DEN-induced mouse liver tumors

Mayhew

Schnekenburger

et al. 2008

Toxicology

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The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the biologic and toxic effects of its xenobiotic ligands. In recent years it has become evident that in the absence of ligand the AHR promotes cell cycle progression and that its activation by high-affinity ligands results in interactions with the retinoblastoma protein (RB) that lead to perturbation of the cell cycle, G 0 /G 1 arrest, diminished capacity for DNA replication and inhibition of cell proliferation. Hence, the AHR has diametrically opposed pro-proliferative and anti-proliferative functions that have yet to be reconciled at the molecular level. Work from our own and from other laboratories suggests that the AHR may function as a tumor suppressor gene that becomes silenced in the process of tumor formation. To develop preliminary support for a more thorough examination of this hypothesis we characterized the expression levels of various tumor suppressor genes, transforming growth factor-β (Tgfb) genes and the Ahr gene in liver tumor samples from mice with a liver-specific RB ablation and their wild-type littermates. In tumors arising in RB-positive livers, Cdkn2d and Tgfb1 were repressed and Cdkn2c, Tgfb2, Tgfb3 and Pai1 were induced, whereas in RB-negative tumors, only Cdkn2c and Tgfb3 were induced. Ahr was significantly repressed in tumors from both sets of mice, supporting the concept that Ahr silencing may be associated with cancer progression.

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Section: Introductionsupporting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Repression of Ah receptor and induction of transforming growth factor-β genes in DEN-induced mouse liver tumors

Mayhew

Schnekenburger

et al. 2008

Toxicology

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“…This enabled us to test various combinations of input DNA using GFP expression as a marker of transfected cells (Strobeck et al, 2000). The ability of these transfected Cyclin D1 protein is normally very unstable with an estimated half-life of 530 min.…”

Section: Cyclin D1 and Er Mediated Proliferationmentioning

confidence: 99%

Involvement of G1/S cyclins in estrogen-independent proliferation of estrogen receptor-positive breast cancer cells

et al. 2002

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Estrogen receptor-mediated transcription is enhanced by overexpression of G1/S cyclins D1, E or A in the presence as well in the absence of estradiol. Excess of G1/S cyclins also prevents the inhibition of transactivation of estrogen receptor (ER) by the pure antiestrogen ICI 182780. Cyclin D1 mediates this transactivation independent of complex formation to its CDK4/6 partner. This raises the possibility that overexpression of G1/S cyclins renders growth of ER-positive breast cancer hormone-independent and resistant to treatment with antiestrogens. Transient transfection of ER-positive breast cancer cell lines T47D and MCF7 with G1/S cyclins could overcome the growth arrest induced by ICI 182780 treatment. The ability of various cyclin D1 mutants to overcome the ICI 182780 mediated growth arrest corresponded with their ability to stimulate cyclin A-and E2F-promoter based reporter activities in the presence of ICI 182780. Transfection of a mutant cyclin D1 (cyclin D1-KE) that was unable to bind CDK4 and was reported to transactivate ER in the presence of ICI 182780, could not stimulate proliferation in ICI 182780 treated cells. On the other hand, cyclin D1-LALA, which is unable to stimulate ERE transactivation, could overcome the ICI 182780 cell cycle arrest. Furthermore, transient transfection of T47D cells using cyclin D1 together with a catalytic inactive mutant of CDK4 (CDK4-DN) indicated that the observed effect is due to binding to CDK inhibitors. However, a moderate, sixfold overexpression of cyclin D1 in stably transfected MCF7 cells did not overcome the ICI 182780 mediated growth arrest. These results indicate that CDK-independent transactivation of the estrogen receptor by cyclin D1 is by itself, not sufficient to result in estradiol-independent growth of breast cancer cells, whereas a vast overexpression of G1/S cyclins is able to do so, most likely by capturing of CDK inhibitors.

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Section: Introductionmentioning

confidence: 99%

“…Most evidence shows that AHR activation delays cell cycle progression and G 1 to S phase transition, although this effect seems to be cellular context specific, because in rat oval progenitor cells the AHR promotes rather than delays cell cycle progression (Weiss et al, 2008). A canonical RB-binding cyclin D-like motif in the AHR protein sequence mediates a direct interaction between AHR and RB, and experimental work focused on the characterization of this interaction as the mediator of AHR-dependent cell cycle delay (Ge and Elferink, 1998;Puga et al, 2000;Marlowe et al, 2004;Huang and Elferink, 2005) has shown that the activated AHR cooperates with RB in its ability to repress E2F-dependent transcription and delay cell cycle progression Strobeck et al, 2000).Paradoxically, embryo fibroblasts from Ahr gene-knockout mice also show a relative delay in cell cycle progression, which has been primarily associated with posttranscriptional stabilization of Tgfb1 mRNA (Chang et al, 2007). In these cells, several E2F transcriptional targets with AHR and E2F binding motifs in their promoters, conserved in both the human and mouse sequences (Supplemental Tables S1 and S2), were also found to be AHR targets, being repressed by both E2f1 and Ahr ablation (Supplemental Figure S1).…”

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confidence: 99%

The Aryl Hydrocarbon Receptor Binds to E2F1 and Inhibits E2F1-induced Apoptosis

Marlowe

Fan

Chang

et al. 2008

MBoC

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Cellular stress by DNA damage induces checkpoint kinase-2 (CHK2)-mediated phosphorylation and stabilization of the E2F1 transcription factor, leading to induction of apoptosis by activation of a subset of proapoptotic E2F1 target genes, including Apaf1 and p73. This report characterizes an interaction between the aryl hydrocarbon (Ah) receptor (AHR), a ligand-activated transcription factor, and E2F1 that results in the attenuation of E2F1-mediated apoptosis. In Ahr ؊/؊ fibroblasts stably transfected with a doxycycline-regulated AHR expression vector, inhibition of AHR expression causes a significant elevation of oxidative stress, ␥H2A.X histone phosphorylation, and E2F1-dependent apoptosis, which can be blocked by small interfering RNA-mediated knockdown of E2F1 expression. In contrast, ligand-dependent AHR activation protects these cells from etoposide-induced cell death. In cells expressing both proteins, AHR and E2F1 interact independently of the retinoblastoma protein (RB), because AHR and E2F1 coimmunoprecipitate from extracts of RBnegative cells. Additionally, chromatin immunoprecipitation assays indicate that AHR and E2F1 bind to the Apaf1 promoter at a region containing a consensus E2F1 binding site but no AHR binding sites. AHR activation represses Apaf1 and TAp73 mRNA induction by a constitutively active CHK2 expression vector. Furthermore, AHR overexpression blocks the transcriptional induction of Apaf1 and p73 and the accumulation of sub-G 0 /G 1 cells resulting from ectopic overexpression of E2F1. These results point to a proproliferative, antiapoptotic function of the Ah receptor that likely plays a role in tumor progression. INTRODUCTIONMembers of the E2F family of transcription factors are critical regulators of the G 1 /S phase transition of the cell cycle, during which their transcriptional activity is generally controlled through interaction with retinoblastoma (RB) family proteins. In addition, E2F proteins have functions beyond the G 1 /S phase transition that impact cell proliferation in a variety of ways (Dimova and Dyson, 2005). The E2F family consists of six extensively characterized and three less wellstudied members. E2F1, -2, and -3a are potent activators of transcription, bind exclusively to RB-p105, and are cyclically expressed during the cell cycle. E2F3b and -4, which can interact with RB-p107 and -p130, and E2F5, which binds only to p130, are poor transcriptional activators, and they function mainly as repressors through their recruitment of RB proteins to E2F-regulated promoters (Dyson, 1998;Nevins, 1998;DeGregori and Johnson, 2006). In general, the E2Fs with transactivator activity promote cell cycle progression, whereas the E2Fs with transrepressor activity function in cell cycle exit and differentiation (Dimova and Dyson, 2005). E2F6-8 are distinct from the other E2F members, lacking the transactivation and RB-binding domains, and they repress transcription in an RB-independent manner (Frolov and Dyson, 2004;DeGregori and Johnson, 2006).The best-characterized function of E2F ...

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Restoration of retinoblastoma mediated signaling to Cdk2 results in cell cycle arrest

Cited by 69 publications

References 51 publications

Repression of Ah receptor and induction of transforming growth factor-β genes in DEN-induced mouse liver tumors

Repression of Ah receptor and induction of transforming growth factor-β genes in DEN-induced mouse liver tumors

Involvement of G1/S cyclins in estrogen-independent proliferation of estrogen receptor-positive breast cancer cells

The Aryl Hydrocarbon Receptor Binds to E2F1 and Inhibits E2F1-induced Apoptosis

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