Spatiotemporal expression of Rhomboid domain containing 2 (Rhbdd2) during rat development

Ferretti, Valeria Alejandra; Canzoneri, Romina; Barbeito, Claudio Gustavo; Croce, María Virginia; Abba, Martı́n C.; Lacunza, Ezequiel

doi:10.1016/j.acthis.2015.06.005

Cited by 3 publications

(6 citation statements)

References 24 publications

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“…Using confocal microscopy, we were able to corroborate the localization of the RHBDD2 proteins at the Golgi apparatus of human breast cancer cells, as was previously determined in mouse-derived cell lines (31,32). We also identified the RHBDD2 proteins associated with V-SNARE transport vesicles involved in different Golgi trafficking processes.…”

Section: Discussionsupporting

confidence: 78%

Alternative splicing variant of RHBDD2 is associated with cell stress response and breast cancer progression

et al. 2018

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RHBDD2 is an intramembrane pseudoprotease member of the Rhomboid superfamily. Our previous studies in breast and colorectal cancer indicate an association between RHBDD2 overexpression and advanced tumor stages. Two alternative transcriptional variants have been described for RHBDD2, which would be encoding for different RHBDD2 protein isoforms. The expression of these RHBDD2 variants/isoforms and its association with breast cancer was the focus of this study. First, expression of RHBDD2 splicing variants was evaluated in normal and breast tumor samples. RHBDD2 variant 2 overexpression was detected in tumors in respect to normal breast tissues at the mRNA and protein levels (P<0.05). Moreover, RHBDD2 variant 2 expression was associated with poor prognostic factors such as basal‑like intrinsic subtype (P<0.05), high proliferation (P<0.01) and long‑term risk‑of‑recurrence (P<0.01) scores. Second, the expression of both variants was evaluated under nutritional‑deprived conditions in breast cancer cell lines. Results demonstrated that RHBDD2 splicing was switched from mRNA variant 1 to variant 2 in association with a significant increment of protein isoform B in response to glucose starvation treatment. Therefore, we propose that the switch from the RHBDD2 variant 1, expressed in normal epithelial cells, to variant 2 occurs as an adaptive phenotype to bypass the stressful tumor microenvironment and promote tumor progression. Finally, the RHBDD2 subcellular localization was corroborated at the Golgi apparatus and their associated v‑SNARE transport vesicles, suggesting a putative new role for RHBDD2 in the protein trafficking of human breast cancer cells.

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Section: Discussionsupporting

confidence: 78%

Alternative splicing variant of RHBDD2 is associated with cell stress response and breast cancer progression

et al. 2018

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“…WWOX mRNA was primarily expressed in differentiated cells. These results were consistent with previous studies in rat mammary gland development and human breast cancer cells, indicating that RHBDD2 is highly expressed in proliferating cells (10,11,28). Co-IP suggested that RHBDD2-WWOX protein interaction primarily occured in the membrane fraction of proliferating cells and decreased in differentiated cells.…”

Section: Discussionsupporting

confidence: 92%

“…Our subsequent study demonstrated that RHBDD2 abrogation in breast cancer cell lines is associated with cell proliferation and modulation of the unfolded protein response pathway (10). Further analysis showed that increased RHBDD2 expression is associated with the proliferative stages of mammary gland development (11), however, the mechanistic role of such upregulation remains to be determined. Recently, high-throughput proteomic approaches identified RHBDD2 as a novel putative interactor of WW domain-containing oxidoreductase (WWOX) (12).…”

Section: Introductionmentioning

confidence: 84%

“…Our previous studies determined that the RHBDD2 gene is overexpressed in advanced stages of breast and colorectal cancer, suggesting a role in tumor progression and chemoresistance to neoadjuvant therapy (8,9,22). Under normal physiological conditions, RHBDD2 expression is detected not only in embryonic and developing rat tissue but also in proliferating adult rat tissue (11). Regarding the mammary gland, increased Rhbdd2 expression is associated with the pregnancy stage (11).…”

Section: Discussionmentioning

confidence: 99%

“…Under normal physiological conditions, RHBDD2 expression is detected not only in embryonic and developing rat tissue but also in proliferating adult rat tissue (11). Regarding the mammary gland, increased Rhbdd2 expression is associated with the pregnancy stage (11). RHBDD2 encodes one of nine known rhomboid pseudoproteases whose functional roles are defined by binding to target proteins (2).…”

Section: Discussionmentioning

confidence: 99%

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RHBDD2‑WWOX protein interaction during proliferative and differentiated stages in normal and breast cancer cells

et al. 2021

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Rhomboid pseudoproteases are catalytically inactive members of the rhomboid superfamily that modulate the traffic, turnover and activity of their target proteins. Rhomboid domain containing 2 (RHBDD2) is a rhomboid family member overexpressed during mammary gland development and advanced stages of breast cancer. Interactome profiling studies have identified RHBDD2 as a novel binding partner of WW domain-containing oxidoreductase (WWOX) protein.The present study characterized the RHBDD2-WWOX interaction in proliferating and differentiated stages of normal mammary and breast cancer cells by co-immunoprecipitation and confocal microscopy. Normal breast and proliferating cancer cells showed significantly increased RHBDD2 mRNA levels compared with their differentiated counterparts. WWOX mRNA was primarily expressed in differentiated cells. WWOX co-precipitated with RHBDD2, indicating that endogenous RHBDD2 and WWOX were physically associated in normal and breast cancer proliferating cells compared with the differentiated stage. Co-localization assays corroborated the co-immunoprecipitation results, demonstrating the RHBDD2-WWOX protein interaction in normal and proliferating breast cancer cells. RHBDD2 harbors a conserved LPPY motif at the C-terminus region that directly interacted with the WW domains of WWOX. Since WWOX serves as an inhibitor of the TGFβ/SMAD3 signaling pathway in breast cells, modulation of SMAD3 target genes was analyzed in proliferating and differentiated mammary cells and in RHBDD2 silencing assays. Increased expression levels of SMAD3-regulated genes were detected in proliferating cells compared with their differentiated counterparts. Follistatin and angiopoietin-like 4 mRNA was significantly downregulated in RHBDD2 transiently silenced cells compared with scrambled control small interfering RNA. Based on these results, WWOX was suggested to be a novel RHBDD2 target protein involved in the modulation of breast epithelial cell proliferation and differentiation.

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RHBDD2 overexpression promotes a chemoresistant and invasive phenotype to rectal cancer tumors via modulating UPR and focal adhesion genes

Palma

Raffa

Garcia-Fabiani

et al. 2020

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Spatiotemporal expression of Rhomboid domain containing 2 (Rhbdd2) during rat development

Cited by 3 publications

References 24 publications

Alternative splicing variant of RHBDD2 is associated with cell stress response and breast cancer progression

Alternative splicing variant of RHBDD2 is associated with cell stress response and breast cancer progression

RHBDD2‑WWOX protein interaction during proliferative and differentiated stages in normal and breast cancer cells

RHBDD2 overexpression promotes a chemoresistant and invasive phenotype to rectal cancer tumors via modulating UPR and focal adhesion genes

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