p53 represses ribosomal gene transcription

Budde, Andreja; Grummt, Ingrid

doi:10.1038/sj.onc.1202402

Cited by 143 publications

(126 citation statements)

References 39 publications

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“…Previous evidence has outlined a role for p53 in the inhibition of ribosome biogenesis, specifically RNA PolI and PolIII. Transcription of pre-rRNA is elevated in cells deficient for, or expressing mutant forms, of p53, indicating that p53 may suppress PolI-dependent transcription of rDNA (Budde and Grummt, 1999). RNA PolI transcription is dependent on formation of an initiation complex containing the co-factors upstream binding factor and SL1.…”

Section: Discussionmentioning

confidence: 99%

Ribosome biogenesis surveillance: probing the ribosomal protein-Mdm2-p53 pathway

2010

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Section: Discussionmentioning

confidence: 99%

Ribosome biogenesis surveillance: probing the ribosomal protein-Mdm2-p53 pathway

2010

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“…Runx2, p53, and pRb all control cell proliferation by regulating cell-cycle progression and mediating cell growth through effects on ribosomal biogenesis (18,19,30,37,38). Abrogation of tumor suppressor pathways controlled by p53 and pRb, which are ubiquitously expressed, results in the development of diverse tumors that are confined to specific tissues (7,8), indicating that lineagespecific mechanisms are involved.…”

Section: Discussionmentioning

confidence: 99%

Runx2 deficiency and defective subnuclear targeting bypass senescence to promote immortalization and tumorigenic potential

Zaidi

Pande

Pratap

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The osteogenic Runt-related (Runx2) transcription factor negatively regulates proliferation and ribosomal gene expression in normal diploid osteoblasts, but is up-regulated in metastatic breast and prostate cancer cells. Thus, Runx2 may function as a tumor suppressor or an oncogene depending on the cellular context. Here we show that Runx2-deficient primary osteoblasts fail to undergo senescence as indicated by the absence of ␤-gal activity and p16 INK4a tumor suppressor expression. Primary Runx2-null osteoblasts have a growth advantage and exhibit loss of p21 WAF1/CIP1 and p19 ARF expression. Reintroduction of WT Runx2, but not a subnuclear targeting-defective mutant, induces both p21 WAF/CIP1 and p19 ARF mRNA and protein resulting in cell-cycle inhibition. Accumulation of spontaneous phospho-H2A.X foci, loss of telomere integrity and the Mre11/Rad50/Nbs1 DNA repair complex, and a delayed DNA repair response all indicate that Runx2 deficiency leads to genomic instability. We propose that Runx2 functions as a tumor suppressor in primary diploid osteoblasts and that subnuclear targeting contributes to Runx2-mediated tumor suppression.cancer ͉ genomic instability ͉ growth control ͉ nuclear organization ͉ osteoblast W hen exposed to inappropriate growth signals, mammalian cells engage in elaborate mechanisms that provide alternative fates to prevent tumorigenesis. These defenses include apoptosis and senescence, which guard against unrestrained proliferation. Several tumor suppressors, including the retinoblastoma protein (pRb), p53, and the products of the INK4b-ARF-INK4a locus (p15-p19-p16), control telomere integrity, cellular senescence, and genomic stability (1-4). Tumors arise when cells override these intrinsic defenses. Cancer cells typically exhibit independence from extrinsic growth signals, lack of senescence or apoptosis, compromised telomeric integrity, and genomic instability, as well as changes in nuclear organization (2, 4-6). However, mice with genetic ablations of tumor suppressors are prone to tumorigenesis that is often lineage-restricted (7, 8). These observations suggest that lineage-specific mechanisms contribute to tumorigenesis.Runt-related (Runx) transcription factors determine cell fate and regulate lineage-specific proliferation and differentiation (9-11). Genetic studies reveal that Runx1 is essential for definitive hematopoiesis, Runx2 is required for osteogenesis, and Runx3 is involved in gut development as well as neurogenesis (12-16). Runx proteins support epigenetic regulation at mitosis and control ribosomal gene expression during the cell cycle (9)(10)(11)(17)(18)(19). Runx transcription factors are nuclear-scaffolding proteins that integrate signaling pathways by organizing macromolecular complexes in nuclear microenvironments and facilitating chromatin remodeling (20). Mice with gene replacements expressing subnuclear targeting defective mutants (mSTDs) of Runx1 or Runx2 from the native loci exhibit phenotypes identical to mice in which the gene has been ablated (21, 22), sugge...

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“…A positive association between AgNOR activity and tumor stage in HD has been reported. 71,72 Regulation of rDNA transcription involves several tumorigenic pathways mediated through key molecules, including RB1 73 and TP53 74 for which a binding site is present downstream of Cb2b3. 46 …”

Section: Possible Roles For Rdna Changesmentioning

confidence: 99%

Karyotypic dissection of Hodgkin's disease cell lines reveals ectopic subtelomeres and ribosomal DNA at sites of multiple jumping translocations and genomic amplification

MacLeod

Spitzer

Bar‐Am³

et al. 2000

Leukemia

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Although the neoplastic significance of the chromosome changes widespread in Hodgkin's disease (HD) remains obscure, a distinct cytogenetic picture has emerged combining aneuploidy with structural rearrangements clustered at certain breakpoints. Notably absent are the recurrent chromosome translocations which distinguish other hematopoietic neoplasms and serve as clues to underlying oncogene alterations. The paucity of neoplastic cells in HD biopsies hinders detailed chromosome analysis. As an alternative, we investigated a panel of well characterized cell lines by classical and molecular cytogenetics, using single-gene and subtelomeric probes, including three autologous HD examples (HDLM-1/2/3) analyzed by 'spectral karyotyping' -the first complete HD karyotype to be documented. Although complex, most rearrangements in HDLM cells arose in vivo and included few rare but many typical HD breakpoints, notably at the r(ibosomal)DNA regions. Two types of genomic rearrangement involving DNA repeats were conspicuous: insertion and genomic amplification/coamplification of rDNA -the first genomic rDNA rearrangements to be reported in a tumor cell, and the first example of multiple 'jumping translocations' (JT). Of four subtelomeric microsatellite repeats tested in HDLM cells, three exhibited interstitial sites at JT, of which two (at 5qter and 9pter) were respectively associated with deletion of the 5q31-32 myeloid region, and coamplification of a recently described HD-recurrent amplicon at 9p2 together with transcriptionally silent rDNA. Altogether, three out of four HD cell lines carried interstitial 9p subtelomeres and rDNA rearrangements. Taken together, these data suggest tumorigenic rearrangements may be facilitated by 'hitchhiking' along with mobile DNA repeat sequences which may target gene rearrangement at 9p in HD. Southern analysis of parallel rearrangements within rDNA intergenic spacers in HDLM cells highlighted several at, or near, retroposons. As well as validating HD cell lines as cytogenetic models, and resources for identifying genes rearranged in HD, our findings warrant further investigation of the roles of DNA repeat sequences, notably subtelomeric microsatellites, rDNA spacer sequences and retroposons as facilitators and markers of tumor-gene rearrangement.

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p53 represses ribosomal gene transcription

Cited by 143 publications

References 39 publications

Ribosome biogenesis surveillance: probing the ribosomal protein-Mdm2-p53 pathway

Ribosome biogenesis surveillance: probing the ribosomal protein-Mdm2-p53 pathway

Runx2 deficiency and defective subnuclear targeting bypass senescence to promote immortalization and tumorigenic potential

Karyotypic dissection of Hodgkin's disease cell lines reveals ectopic subtelomeres and ribosomal DNA at sites of multiple jumping translocations and genomic amplification

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