Ribosomal 18 S RNA Processing by the IGF-I-responsive WDR3 Protein Is Integrated with p53 Function in Cancer Cell Proliferation

McMahon, Mary; Ayllón, Verónica; Panov, Kostya I.; O’Connor, Rosemary

doi:10.1074/jbc.m110.108555

Cited by 35 publications

(45 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This would agree with the studies carried out in the breast carcinoma cell line MCF-7 showing that the suppression of WDR3 reduce cell proliferation, decrease cell size and reduce foci formation, indicating that WDR3 confers a growth and proliferative advantage on cancer cells [8]. The WDR3 protein is redistributed within the nucleus when ribosome biogenesis is disrupted.…”

Section: Discussionsupporting

confidence: 91%

Possible Role of the WDR3 Gene on Genome Stability in Thyroid Cancer Patients

et al. 2012

View full text Add to dashboard Cite

The role of the WDR3 gene on genomic instability has been evaluated in a group of 115 differentiated thyroid cancer (DTC) patients. Genomic instability has been measured according to the response of peripheral blood lymphocytes to ionizing radiation (0.5 Gy). The response has been measured with the micronucleus (MN) test evaluating the frequency of binucleated cells with MN (BNMN), both before and after the irradiation. No differences between genotypes, for the BNMN frequencies previous the irradiation, were observed. Nevertheless significant decreases in DNA damage after irradiation were observed in individuals carrying the variant alleles for each of the three genotyped SNPs: rs3754127 [−8.85 (−15.01 to −2.70), P<0.01]; rs3765501 [−8.98 (−15.61 to −2.36), P<0.01]; rs4658973 [−8.70 (−14.94 to −2.46), P<0.01]. These values correspond to those obtained assuming a dominant model. This study shows for the first time that WDR3 can modulate genome stability.

show abstract

Section: Discussionsupporting

confidence: 91%

Possible Role of the WDR3 Gene on Genome Stability in Thyroid Cancer Patients

et al. 2012

View full text Add to dashboard Cite

show abstract

“…The snoRNA U70C resides in an intron of the Astrotactin 2 (ASTN2) gene in the sense orientation and it serves as a guide for the pseudouridylation of selected bases of rRNA by forming short duplexes with the 18S rRNA U1692, the target for this snoRNA 50 , 52 , 53 . A role for 18S rRNA in tumorigenesis is starting to emerge, 54 - 56 and our findings provide additional information about this role.…”

Section: Resultsmentioning

confidence: 63%

CpG island hypermethylation-associated silencing of small nucleolar RNAs in human cancer

et al. 2012

View full text Add to dashboard Cite

Much effort in cancer research has focused on the tiny part of our genome that codes for mRNA. However, it has recently been recognized that microRNAs also contribute decisively to tumorigenesis. Studies have also shown that epigenetic silencing by CpG island hypermethylation of microRNAs with tumor suppressor activities is a common feature of human cancer. The importance of other classes of non-coding RNAs, such as long intergenic ncRNAs (lincRNAs) and transcribed ultraconserved regions (T-UCRs) as altered elements in neoplasia, is also gaining recognition. Thus, we wondered whether there were other ncRNAs undergoing CpG island hypermethylation-associated inactivation in cancer cells. We focused on the small nucleolar RNAs (snoRNAs), a subset of ncRNA with a wide variety of cellular functions, such as chemical modification of RNA, pre-RNA processing and control of alternative splicing. By data mining snoRNA databases and the scientific literature, we selected 49 snoRNAs that had a CpG island within ≤ 2 Kb or that were processed from a host gene with a 5′-CpG island. Bisulfite genomic sequencing of multiple clones in normal colon mucosa and the colorectal cancer cell line HCT-116 showed that 46 snoRNAs were equally methylated in the two samples: completely unmethylated (n = 26) or fully methylated (n = 20). Most interestingly, the host gene-associated 5′-CpG islands of the snoRNAs SNORD123, U70C and ACA59B were hypermethylated in the cancer cells but not in the corresponding normal tissue. CpG island hypermethylation was associated with the transcriptional silencing of the respective snoRNAs. Results of a DNA methylation microarray platform in a comprehensive collection of normal tissues, cancer cell lines and primary malignancies demonstrated that the observed hypermethylation of snoRNAs was a common feature of various tumor types, particularly in leukemias. Overall, our findings indicate the existence of a new subclass of ncRNAs, snoRNAs, that are targeted by epigenetic inactivation in human cancer.

show abstract

“…Alternatively, TTRAP-mediated downregulation of pre-rRNA levels may be secondary to its role in rRNA processing, as already postulated for other non-ribosomal proteins involved in rRNA biogenesis. 36 In summary, these data provide the first evidence for the involvement of nucleolar cavities and TTRAP in ribosome biogenesis and support the need for a better understanding of their roles in cellular responses to stress in neurodegeneration and oncogenesis.…”

Section: Discussionmentioning

confidence: 91%

The PML nuclear bodies-associated protein TTRAP regulates ribosome biogenesis in nucleolar cavities upon proteasome inhibition

et al. 2011

View full text Add to dashboard Cite

TRAF and TNF receptor-associated protein (TTRAP) is a multifunctional protein that can act in the nucleus as a 5 0 -tyrosyl DNA phosphodiesterase and in the cytoplasm as a regulator of cell signaling. In this paper we show that in response to proteasome inhibition TTRAP accumulates in nucleolar cavities in a promyelocytic leukemia protein-dependent manner. In the nucleolus, TTRAP contributes to control levels of ribosomal RNA precursor and processing intermediates, and this phenotype is independent from its 5 0 -tyrosyl DNA phosphodiesterase activity. Our findings suggest a previously unidentified function for TTRAP and nucleolar cavities in ribosome biogenesis under stress. Cell Death and Differentiation (2012) 19, 488-500; doi:10.1038/cdd.2011; published online 16 September 2011 TRAF and TNF receptor-associated protein (TTRAP) is a 5 0 -tyrosyl DNA phosphodiesterase that is required for the repair of topoisomerase2-induced DNA double-strand breaks. 1 It is a member of the endonuclease/exonuclease/ phosphatase family of proteins containing an Mg(2 þ )-dependent apurinic/apyrimidinic endonuclease Ape1-like domain. 2 Various yeast-two hybrid (Y2H) screenings and functional studies have unveiled TTRAP ability to interact with TNF receptors (TNFR) family members and TNFR-associated factors (TRAFs), especially TRAF6. 3 Furthermore, TTRAP was isolated as ETS-associated protein II 4 and as alk4-and smad3-binding protein. 5 Interestingly, TTRAP sequence contains a SUMO-interacting motif (SIM) that is required for its high affinity binding to SUMO-2/3. 6 TTRAP may thus has a role in the cytoplasm as a signaling molecule and in the nucleus as a DNA damage response protein and transcriptional regulator. In this context, its potential interaction with promyelocytic leukemia protein (PML), as previously determined in Y2H, suggests that TTRAP is a PML nuclear bodies (PML-NBs)-associated protein. 7 It remains unclear whether its 5 0 -tyrosyl DNA phosphodiesterase activity may account for all TTRAP biological functions.According to the cellular context, TTRAP may either protect cells from apoptosis or promote death. [8][9][10] When human SH-SY5Y cells are stressed by low doses of proteasome inhibitors, TTRAP is neuroprotective. In these conditions, endogenous TTRAP relocalizes to the cytoplasm and forms aggresome-like inclusions.In this paper we show that in response to high doses of proteasome inhibitors, TTRAP localizes to the nucleolus. This accumulation requires the association to PML-NBs and occurs in nucleolar cavities, a compartment devoid of markers of the 'ribosomal nucleolus'. Lack of TTRAP alters the levels of precursor ribosomal RNA (pre-rRNA) and processing intermediates, suggesting a new role of the PML-NBs-associated protein TTRAP in rRNA biogenesis. This function is dependent on TTRAP SIM motif, but is independent from its 5 0 -tyrosyl DNA phosphodiesterase activity. Altogether, these data suggest a novel function for TTRAP and nucleolar cavities in controlling rRNA biogenesis in response to proteasome inhibiti...

show abstract

Ribosomal 18 S RNA Processing by the IGF-I-responsive WDR3 Protein Is Integrated with p53 Function in Cancer Cell Proliferation

Abstract: Insulin-like growth factor-I (IGF-I

Cited by 35 publications

References 48 publications

Possible Role of the WDR3 Gene on Genome Stability in Thyroid Cancer Patients

Possible Role of the WDR3 Gene on Genome Stability in Thyroid Cancer Patients

CpG island hypermethylation-associated silencing of small nucleolar RNAs in human cancer

The PML nuclear bodies-associated protein TTRAP regulates ribosome biogenesis in nucleolar cavities upon proteasome inhibition

Contact Info

Product

Resources

About