Rb and p130 regulate RNA polymerase I transcription: Rb disrupts the interaction between UBF and SL-1

Hannan, K M; Hannan, Ross D.; Smith, S D; Jefferson, Leonard S.; Lun, Mingyue; Rothblum, Lawrence I.

doi:10.1038/sj.onc.1203875

Cited by 122 publications

(88 citation statements)

References 56 publications

(133 reference statements)

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“…7), consistent with a role for the Rb family of proteins in the regulation of rDNA transcription (Ciarmatori et al, 2001;Hannan et al, 2000). We, however, did not find any cells in the entire exponentially growing population (Figs 6, 7), which exhibited the limited perinucleolar pRb staining pattern described by Kennedy et al (Kennedy et al, 2000).…”

Section: Journal Of Cell Science 115 (21)mentioning

confidence: 46%

The spatio-temporal organization of DNA replication sites is identical in primary, immortalized and transformed mammalian cells

Dimitrova

Berezney

2002

Journal of Cell Science

206

176

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We investigated the organization of DNA replication sites in primary (young or presenescent), immortalized and transformed mammalian cells. Four different methods were used to visualize replication sites: in vivo pulse-labeling with 5-bromo-2′-deoxyuridine (BrdU), followed by either acid depurination, or incubation in nuclease cocktail to expose single-stranded BrdU-substituted DNA regions for immunolabeling; biotin-dUTP labeling of nascent DNA by run-on replication within intact nuclei and staining with fluorescent streptavidin;and, finally, immunolabeling of the replication fork proteins PCNA and RPA. All methods produced identical results, demonstrating no fundamental differences in the spatio-temporal organization of replication patterns between primary, immortal or transformed mammalian cells. In addition, we did not detect a spatial coincidence between the early firing replicons and nuclear lamin proteins, the retinoblastoma protein or the nucleolus in primary human and rodent cells. The retinoblastoma protein does not colocalize in vivo with members of the Mcm family of proteins (Mcm2, 3 and 7) at any point of the cell cycle and neither in the chromatin-bound nor in the soluble nucleoplasmic fraction. These results argue against a direct role for the retinoblastoma or nuclear lamin proteins in mammalian DNA synthesis under normal physiological conditions.

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Section: Journal Of Cell Science 115 (21)mentioning

confidence: 46%

The spatio-temporal organization of DNA replication sites is identical in primary, immortalized and transformed mammalian cells

Dimitrova

Berezney

2002

Journal of Cell Science

206

176

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“…Our data indicate that disruption of the SL1/rDNA complex by CX-5461 results from the interference between SL1 and rDNA and not through dissociation of protein-protein interactions, as was shown for several known tumor suppressors (p53, Rb, PTEN; refs. [32][33][34].…”

Section: Discussionmentioning

confidence: 99%

Targeting RNA Polymerase I with an Oral Small Molecule CX-5461 Inhibits Ribosomal RNA Synthesis and Solid Tumor Growth

et al. 2011

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Deregulated ribosomal RNA synthesis is associated with uncontrolled cancer cell proliferation. RNA polymerase (Pol) I, the multiprotein complex that synthesizes rRNA, is activated widely in cancer. Thus, selective inhibitors of Pol I may offer a general therapeutic strategy to block cancer cell proliferation. Coupling medicinal chemistry efforts to tandem cell-and molecular-based screening led to the design of CX-5461, a potent small-molecule inhibitor of rRNA synthesis in cancer cells. CX-5461 selectively inhibits Pol I-driven transcription relative to Pol II-driven transcription, DNA replication, and protein translation. Molecular studies demonstrate that CX-5461 inhibits the initiation stage of rRNA synthesis and induces both senescence and autophagy, but not apoptosis, through a p53-independent process in solid tumor cell lines. CX-5461 is orally bioavailable and demonstrates in vivo antitumor activity against human solid tumors in murine xenograft models. Our findings position CX-5461 for investigational clinical trials as a potent, selective, and orally administered agent for cancer treatment.

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“…It has been reported that pRb can be found in the nucleolus of quiescent or differentiating cells, where it binds UBF1 and causes a decrease in transcription from the rDNA promoter (29)(30)(31). It has also been reported that pRb binds to the pRb binding motif (LxCxE) of UBF1 (29), but subsequent reports have indicated that pRb binds to a different sequence of UBF1 (30). We first determined whether IRS-1 and pRb competed directly for binding to UBF1, and then we tested whether the expression of IRS-1 inhibited the occupancy of the rDNA promoter by pRb.…”

Section: Cancer Researchmentioning

confidence: 99%

Insulin Receptor Substrate-1 Regulates the Transformed Phenotype of BT-20 Human Mammary Cancer Cells

Dalmızrak

Chen

et al. 2007

Cancer Research

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Although originating from a human breast cancer, BT-20 cells do not form colonies in soft agar. BT-20 cells do not express insulin receptor substrate-1 (IRS-1), which is known to promote both normal and abnormal growth and to inhibit differentiation. Stable expression of IRS-1 confers to BT-20 cells the ability to form colonies in soft agar. BT-20 cells form tumors in xenografts in mice, but the size of tumors is twice as large when the cells express IRS-1. The increased transformed phenotype is characterized by occupancy of the rDNA and cyclin D1 promoters by IRS-1 and the activation of the cyclin D1, c-myc, and rDNA promoters. In addition, the retinoblastoma protein, which is detectable in the rDNA promoter of quiescent BT-20/IRS-1 cells, is replaced by IRS-1 after insulinlike growth factor-I stimulation. Our results indicate that in BT-20 human mammary cancer cells, expression of IRS-1 activates promoters involved in cell growth and cell proliferation, resulting in a more transformed phenotype. Targeting of IRS-1 could be effective in inhibiting the proliferation of mammary cancer cells. [Cancer Res 2007;67(5):2124-30]

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Rb and p130 regulate RNA polymerase I transcription: Rb disrupts the interaction between UBF and SL-1

Cited by 122 publications

References 56 publications

The spatio-temporal organization of DNA replication sites is identical in primary, immortalized and transformed mammalian cells

The spatio-temporal organization of DNA replication sites is identical in primary, immortalized and transformed mammalian cells

Targeting RNA Polymerase I with an Oral Small Molecule CX-5461 Inhibits Ribosomal RNA Synthesis and Solid Tumor Growth

Insulin Receptor Substrate-1 Regulates the Transformed Phenotype of BT-20 Human Mammary Cancer Cells

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