Molecular mechanisms underlying WOX1 activation during apoptotic and stress responses

Chang, Nan Shan; Doherty, Joan; Ensign, Amy; Lewis, Jennifer; Heath, John K.; Schultz, Lori; Chen, Shur Tzu; Oppermann, U.

doi:10.1016/s0006-2952(03)00484-2

Cited by 72 publications

(100 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, at high doses estrogen may induce apoptosis (Song and Santen, 2003;review). We do not exclude the possibility that at a physiologic concentration, WOX1 is antiapoptotic and essential for cell survival (Chang et al, 2003b).…”

Section: Discussionmentioning

confidence: 91%

“…Indeed, a large portion of the phosphorylated WOX1 is present in the mitochondria, suggesting its role in homeostasis in these organelles. WOX1 possesses a conserved NSYK motif that may interact with estrogen and androgen (Chang et al, 2003b). The increased Tyr33-phosphorylation suggests activation of WOX1 by sex hormones in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…WOX1 has been shown to be a candidate tumor suppressor and a proapoptotic protein (Richards, 2001;Chang, 2002a;Chang et al, 2003b;reviews). The full-length WOX1 possesses two N-terminal WW domains (containing conserved tryptophan residues), a nuclear localization sequence (NLS), and a C-terminal short-chain alcohol dehydrogenase/reductase (SDR) domain (Chang et al, 2003b). There are at least eight alternatively transcribed mRNAs of WWOX gene (Chang et al, 2003b).…”

Section: Introductionmentioning

confidence: 99%

“…The full-length WOX1 possesses two N-terminal WW domains (containing conserved tryptophan residues), a nuclear localization sequence (NLS), and a C-terminal short-chain alcohol dehydrogenase/reductase (SDR) domain (Chang et al, 2003b). There are at least eight alternatively transcribed mRNAs of WWOX gene (Chang et al, 2003b). Whether these transcripts can be translated successfully into proteins are unknown.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

17β-Estradiol upregulates and activates WOX1/WWOXv1 and WOX2/WWOXv2 in vitro: potential role in cancerous progression of breast and prostate to a premetastatic state in vivo

et al. 2004

Self Cite

View full text Add to dashboard Cite

Human WWOX gene encodes a proapoptotic WW domaincontaining oxidoreductase WOX1 (also named WWOX, FOR2 or WWOXv1). Apoptotic and stress stimuli activate WOX1 via Tyr33 phosphorylation and nuclear translocation. WOX1 possesses a tetrad NSYK motif in the Cterminal short-chain alcohol dehydrogenase/reductase (SDR) domain, which may bind estrogen and androgen. Here, we determined that 17b-estradiol (E 2 ) activated WOX1, p53 and ERK in COS7 fibroblasts, primary lung epithelial cells, and androgen receptor (AR)-negative prostate DU145 cells, but not in estrogen receptor (ER)-positive breast MCF7 cells. Androgen also activated WOX1 in the AR-negative DU145 cells. These observations suggest that sex hormone-mediated Tyr33 phosphorylation and nuclear translocation of WOX1 is independent of ER and AR. Stress stimuli increase physical binding of p53 with WOX1 in vivo. We determined here that E 2 increased the formation of p53/WOX1 complex and their nuclear translocation in COS7 cells; however, nuclear translocation of this complex could not occur in MCF7 cells. By immunohistochemistry, we determined that progression of prostate from normal to hyperplasia, cancerous and metastatic stages positively correlate with upregulation and activation of WOX1 and WOX2 (FOR1/WWOXv2). In contrast, breast cancer development to a premetastatic state is associated with upregulation and Tyr33 phosphorylation of cytosolic WOX1 and WOX2, followed by significant downregulation or absent expression during metastasis. These Tyr33-phosphorylated proteins are mostly located in the mitochondria without translocating to the nuclei, which is comparable to those findings in cultured breast cancer cells. Together, sex steroid hormone-induced activation of WOX1 and WOX2 is independent of ER and AR, and this activation positively correlates with cancerous progression of prostate and breast to a premetastatic state.

show abstract

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

17β-Estradiol upregulates and activates WOX1/WWOXv1 and WOX2/WWOXv2 in vitro: potential role in cancerous progression of breast and prostate to a premetastatic state in vivo

et al. 2004

Self Cite

View full text Add to dashboard Cite

show abstract

“…The C1q binding with its receptor leads to the phosphorylation and consequent activation of WWOX, which is a known oncosuppressor required to block cancer cell proliferation. 15 Indeed, activated WWOX may induce the apoptosis of mammary tumor cancer cells, probably by interacting with p53, 48 and inhibit the EMT processes through the expression of E-Cadherin. Conversely, the lack of C1q prevents WWOX activation leading to tumor cell growth and metastases formation.…”

Section: Discussionmentioning

confidence: 99%

The non-inflammatory role of C1q during Her2/neu-driven mammary carcinogenesis

et al. 2016

View full text Add to dashboard Cite

There is an ever increasing amount of evidence to support the hypothesis that complement C1q, the first component of the classical complement pathway, is involved in the regulation of cancer growth, in addition to its role in fighting infections. It has been demonstrated that C1q is expressed in the microenvironment of various types of human tumors, including breast adenocarcinomas. This study compares carcinogenesis progression in C1q deficient (neuT-C1KO) and C1q competent neuT mice in order to investigate the role of C1q in mammary carcinogenesis. Significantly accelerated autochthonous neu C carcinoma progression was paralleled by accelerated spontaneous lung metastases occurrence in C1q deficient mice. Surprisingly, this effect was not caused by differences in the tumor-infiltrating cells or in the activation of the complement classical pathway, since neuT-C1KO mice did not display a reduction in C3 fragment deposition at the tumor site. By contrast, a significant higher number of intratumor blood vessels and a decrease in the activation of the tumor suppressor WW domain containing oxidoreductase (WWOX) were observed in tumors from neuT-C1KO as compare with neuT mice. In parallel, an increase in Her2/neu expression was observed on the membrane of tumor cells. Taken together, our findings suggest that C1q plays a direct role both on halting tumor angiogenesis and on inducing apoptosis in mammary cancer cells by coordinating the signal transduction pathways linked to WWOX and, furthermore, highlight the role of C1q in mammary tumor immune surveillance regardless of complement system activation.Abbreviations: BALB-C1KO, BALB/c mice deficient for the C1qA; BALB-C3KO, BALB/c mice deficient for C3; C1KO, C1q deficient; C1qR, C1q receptor; CR3, complement receptor 3; EMT, epithelial-to-mesenchymal transition; KLRK1 or NKG2D, killer cell lectin-like receptor subfamily K, member 1; MDCS, myeloid-derived suppressor cells; neuT, rat Her2/neu transgenic; neuT-BKO mice, neuT mice deficient in antibody production; neuT-C1KO mice, neuT mice deficient for the C1qA molecule; neuT-C3KO mice, neuT mice deficient for the C3 molecule; NK, natural killer; pWWOX, phospho WWOX; Treg, T regulatory; WWOX, WW domain containing oxidoreductase

show abstract

Chromosomal fragile sites FRA3B and FRA16D show correlated expression and association with failure of apoptosis in lymphocytes from patients with thyroid cancer

Sbrana

Veroni

Nieri

et al. 2006

Genes Chromosomes & Cancer

View full text Add to dashboard Cite

It has been suggested that common fragile sites (cFSs) are related to cancer development. This appears to be the case for FRA3B and FRA16D, localized in two tumor-suppressor genes (FHIT and WWOX, respectively) that are altered by deletions or loss of heterozygosity (LOH) in many cancers. The features responsible for fragility have not yet been identified. Furthermore, it is still unclear whether instability at these regions causes chance deletions and loss of function of the associated genes, or whether the gene function itself is related to the appearance of fragility. In this study, we analyzed cFS expression in lymphocytes from 20 healthy or thyroid cancer-affected subjects exposed to radiation after the Chernobyl accident. The same cells were examined for apoptosis, a principal function of both the FHIT and WWOX genes. Exceptionally elevated chromosome fragility was observed, particularly in cancer patients, affecting FRA3B, FRA16D, and a cluster of less highly expressed cFSs; levels of chromosome fragility were found to be correlated among these cFSs. Interestingly, most expressed cFSs were sites of LOH reported for thyroid tumors; moreover, cells with the highest fragility also had a reduced ability to undergo apoptosis. These findings reveal previously unknown genetic interactions affecting fragile loci, suggestive of a shared function inside mitotic cells. Attenuation of checkpoint control and apoptosis resistance seem to be the cell phenotypes associated with unusual chromosome fragility. We propose that breakage at specific cFS could derive from early epigenetic events at loci involved in radiation carcinogenesis. This article contains supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.

show abstract

Molecular mechanisms underlying WOX1 activation during apoptotic and stress responses

Cited by 72 publications

References 38 publications

17β-Estradiol upregulates and activates WOX1/WWOXv1 and WOX2/WWOXv2 in vitro: potential role in cancerous progression of breast and prostate to a premetastatic state in vivo

17β-Estradiol upregulates and activates WOX1/WWOXv1 and WOX2/WWOXv2 in vitro: potential role in cancerous progression of breast and prostate to a premetastatic state in vivo

The non-inflammatory role of C1q during Her2/neu-driven mammary carcinogenesis

Chromosomal fragile sites FRA3B and FRA16D show correlated expression and association with failure of apoptosis in lymphocytes from patients with thyroid cancer

Contact Info

Product

Resources

About