Ubc9-induced inhibition of diadenosine triphosphate hydrolase activity of the putative tumor suppressor protein Fhit

Gołębiowski, Filip; Szulc, Aneta; Szutowicz, Andrzej; Pawełczyk, Tadeusz

doi:10.1016/j.abb.2004.05.020

Cited by 27 publications

(21 citation statements)

References 27 publications

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“…Exons 5 -9 code for a small mRNA of 1.1 kb, which is susceptible to modification by alternative splicing and downregulation by promoter methylation. The FHIT protein (16.8 kDa) is mainly localised in the cytoplasm of epithelial cells complexed with tubulin and a ubiquitin conjugating enzyme, UBC9 (Shi et al, 2000;Golebiowski et al, 2004). Experimental results have shown that FHIT protein functions as a hydrolase for intracellular diadenosine triphosphate that is involved in the control of cell growth.…”

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confidence: 99%

The expression of FHIT, PCNA and EGFR in benign and malignant breast lesions

Terry

Londesborough

et al. 2006

Br J Cancer

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Immunohistochemical staining for FHIT and PCNA proteins was carried out in 451 breast lesions showing nonproliferative benign breast disease (BBD) (n ¼ 263), proliferative BBD without atypia (n ¼ 128), proliferative BBD with atypia (n ¼ 11), carcinoma in situ (n ¼ 15) or invasive carcinoma (n ¼ 34) and for EGFR protein in a subset of 71 of these cases. FHIT underexpression was not detected in nonproliferative lesions, but occurred in 2% of proliferative BBD without atypia, 10% proliferative BBD with atypia, 27% of carcinoma in situ and 41% of invasive carcinoma, which suggests that it could be useful in assessing those carcinoma in situ lesions (ductal, DCIS and lobular, LCIS) that are more likely to progress to malignancy. Preliminary microarray comparisons on DCIS and invasive carcinoma samples dissected from formalin-fixed paraffin sections showed a consistent downregulation of two previously identified FHIT-related genes, caspase 1 and BRCA1 in lesions underexpressing FHIT.

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confidence: 99%

The expression of FHIT, PCNA and EGFR in benign and malignant breast lesions

Terry

Londesborough

et al. 2006

Br J Cancer

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“…Ubc9 functions as a corepressor (41) or a coactivator (42) of chicken ovalbumin upstream promoter-transcription factor I as tested on two different promoters, always in a manner distinct from its SUMO-1-conjugating activity. Finally, Ubc9 interaction also suppresses the dinucleoside polyphosphate hydrolase activity of the antitumoral protein Fhit irrespective of the addition of SUMO-1 in the assays (21).…”

Section: Discussionmentioning

confidence: 94%

Functional Interaction between Human Herpesvirus 6 Immediate-Early 2 Protein and Ubiquitin-Conjugating Enzyme 9 in the Absence of Sumoylation

Tomoiu

Gravel

Tanguay

et al. 2006

J Virol

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The immediate-early 2 (IE2) protein of human herpesvirus 6 is a potent transactivator of cellular and viral promoters. To better understand the biology of IE2, we generated a LexA-IE2 fusion protein and screened, using the yeast two-hybrid system, a Jurkat T-cell cDNA library for proteins that could interact with IE2. The most frequently isolated IE2-interacting protein was the human ubiquitin-conjugating enzyme 9 (Ubc9), a protein involved in the small ubiquitin-like modifier (SUMO) conjugation pathway. Using deletion mutants of IE2, we mapped the IE2-Ubc9-interacting region to residues 989 to 1037 of IE2. The interaction was found to be of functional significance to IE2, as Ubc9 overexpression significantly repressed promoter activation by IE2. The C93S Ubc9 mutant exhibited a similar effect on IE2, indicating that the E2 SUMO-conjugating function of Ubc9 is not required for its repressive action on IE2. No consensus sumoylation sites or evidence of IE2 conjugation to SUMO could be demonstrated under in vivo or in vitro conditions. Moreover, expression levels and nuclear localization of IE2 were not altered by Ubc9 overexpression, suggesting that Ubc9's repressive function likely occurs at the transcriptional complex level. Overall, our results indicate that Ubc9 influences IE2's function and provide new information on the complex interactions that occur between herpesviruses and the sumoylation pathway.

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“…Further studies are needed to discover the mechanism(s) underlying Fhit shuttling in and out of the nucleus. The interaction between Fhit and Ubc9 (Shi et al, ; Golebiowski et al, ) has pointed to SUMOylation of Fhit by Ubc9 as a post‐translational modification targeting Fhit to the nucleus. We observed that Fhit physically interacts with Ubc9 in chronic proliferative conditions induced by the overexpression of Src (data not shown), raising the possibility that the binding of Fhit to Ubc9 and subsequent Fhit‐SUMOylation represents a nuclear translocation mechanism.…”

Section: Discussionmentioning

confidence: 99%

Fhit Nuclear Import Following EGF Stimulation Sustains Proliferation of Breast Cancer Cells

Bianchi

Sasso

Turdo

et al. 2015

Journal Cellular Physiology

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The tumor-suppressor protein fragile histidine triad (Fhit) exerts its functions in the cytoplasm, although some reports suggest that it may also act in the nucleus. We previously showed that cytosolic Fhit protein levels in cancer cell lines stimulated to proliferate were reduced by proteasomal degradation. Here, we demonstrate that Fhit is physiologically present in the nucleus of breast cancer cell lines and tissues at a low level and that proliferative stimulation increases nuclear levels. Breast cancer cells expressing the FhitY114F mutant, which do not undergo proteasomal degradation, contained mutated Fhit in the nucleus, while cells treated with a proteasome inhibitor accumulated nuclear Fhit during proliferation. Thus, Fhit nuclear shuttling and proteasome degradation phenomena occur independently. When Fhit was coupled to a nuclear localization sequence, the proliferation rate of the transfected cells increased together with levels of proliferation pathway mediators cyclin D1, phospho-MAPK, and phospho-STAT3. Fhit nuclear translocation upon mitogenic stimulation may represent a new regulatory mechanism that allows rapid restoration of Fhit cytoplasmic levels and promotes the proliferation cascade activated by mitogenic stimulation.

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Ubc9-induced inhibition of diadenosine triphosphate hydrolase activity of the putative tumor suppressor protein Fhit

Cited by 27 publications

References 27 publications

The expression of FHIT, PCNA and EGFR in benign and malignant breast lesions

The expression of FHIT, PCNA and EGFR in benign and malignant breast lesions

Functional Interaction between Human Herpesvirus 6 Immediate-Early 2 Protein and Ubiquitin-Conjugating Enzyme 9 in the Absence of Sumoylation

Fhit Nuclear Import Following EGF Stimulation Sustains Proliferation of Breast Cancer Cells

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