Wwox Deficiency Causes Downregulation of Prosurvival ERK Signaling and Abnormal Homeostatic Responses in Mouse Skin

Chou, Ying Tsen; Lai, Feng‐Jie; Chang, Nan Shan; Hsu, Li Jin

doi:10.3389/fcell.2020.558432

Cited by 6 publications

(5 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Compared to wild type MEF cells, knockout MEF cells have a significantly increased rate of proliferation 37 . Similar observations are also shown in skin keratinocytes 56 . TGF-β upregulates F-actin bundles in cytoplasm in a WWOX-dependent manner, suggesting that WWOX is needed for the F-actin bundle formation 57 .…”

Section: Discussionsupporting

confidence: 86%

Normal cells repel WWOX-negative or -dysfunctional cancer cells via WWOX cell surface epitope 286-299

et al. 2021

Self Cite

View full text Add to dashboard Cite

Metastatic cancer cells are frequently deficient in WWOX protein or express dysfunctional WWOX (designated WWOXd). Here, we determined that functional WWOX-expressing (WWOXf) cells migrate collectively and expel the individually migrating WWOXd cells. For return, WWOXd cells induces apoptosis of WWOXf cells from a remote distance. Survival of WWOXd from the cell-to-cell encounter is due to activation of the survival IκBα/ERK/WWOX signaling. Mechanistically, cell surface epitope WWOX286-299 (repl) in WWOXf repels the invading WWOXd to undergo retrograde migration. However, when epitope WWOX7-21 (gre) is exposed, WWOXf greets WWOXd to migrate forward for merge. WWOX binds membrane type II TGFβ receptor (TβRII), and TβRII IgG-pretreated WWOXf greet WWOXd to migrate forward and merge with each other. In contrast, TβRII IgG-pretreated WWOXd loses recognition by WWOXf, and WWOXf mediates apoptosis of WWOXd. The observatons suggest that normal cells can be activated to attack metastatic cancer cells. WWOXd cells are less efficient in generating Ca2+ influx and undergo non-apoptotic explosion in response to UV irradiation in room temperature. WWOXf cells exhibit bubbling cell death and Ca2+ influx effectively caused by UV or apoptotic stress. Together, membrane WWOX/TβRII complex is needed for cell-to-cell recognition, maintaining the efficacy of Ca2+ influx, and control of cell invasiveness.

show abstract

Section: Discussionsupporting

confidence: 86%

Normal cells repel WWOX-negative or -dysfunctional cancer cells via WWOX cell surface epitope 286-299

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…Skin integrity is crucial for the survival of organisms as it acts as a barrier against various environmental factors. One study showed that WWOX protein is expressed in human epidermal suprabasal cells, and its expression progressively intensifies as the cells undergo differentiation towards the superficial layers [ 47 ]. WWOX is also involved in various biological processes, including bubbling apoptosis, transcription, RNA processing, and genomic stability, suggesting that WWOX plays a critical role in normal cellular/physiological homeostasis maintenance [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Mechanistic Investigation of WWOX Function in NF-kB-Induced Skin Inflammation in Psoriasis

Shin,

Kim,

Lee

et al. 2023

IJMS

View full text Add to dashboard Cite

Psoriasis is a chronic inflammatory skin disease characterized by epidermal hyperproliferation, aberrant differentiation of keratinocytes, and dysregulated immune responses. WW domain-containing oxidoreductase (WWOX) is a non-classical tumor suppressor gene that regulates multiple cellular processes, including proliferation, apoptosis, and migration. This study aimed to explore the possible role of WWOX in the pathogenesis of psoriasis. Immunohistochemical analysis showed that the expression of WWOX was increased in epidermal keratinocytes of both human psoriatic lesions and imiquimod-induced mice psoriatic model. Immortalized human epidermal keratinocytes were transduced with a recombinant adenovirus expressing microRNA specific for WWOX to downregulate its expression. Inflammatory responses were detected using Western blotting, real-time quantitative reverse transcription polymerase chain reaction (PCR), and enzyme-linked immunosorbent assay. In human epidermal keratinocytes, WWOX knockdown reduced nuclear factor-kappa B signaling and levels of proinflammatory cytokines induced by polyinosinic: polycytidylic acid [(poly(I:C)] in vitro. Furthermore, calcium chelator and protein kinase C (PKC) inhibitors significantly reduced poly(I:C)-induced inflammatory reactions. WWOX plays a role in the inflammatory reaction of epidermal keratinocytes by regulating calcium and PKC signaling. Targeting WWOX could be a novel therapeutic approach for psoriasis in the future.

show abstract

“…Human dermal fibroblasts were purchased from Lonza (Basel, Switzerland). Lentivirus-mediated gene knockdown was performed as described previously [ 41 ] using the sequences listed in Supplementary Table 1. 5-Azacytidine (5-Aza) was obtained from MedChemExpress (#HY-10586; Monmouth Junction, NJ, USA).…”

Section: Methodsmentioning

confidence: 99%

Loss of fragile WWOX gene leads to senescence escape and genome instability

Cheng,

Huang,

Lai

et al. 2023

Cell. Mol. Life Sci.

Self Cite

View full text Add to dashboard Cite

Induction of DNA damage response (DDR) to ensure accurate duplication of genetic information is crucial for maintaining genome integrity during DNA replication. Cellular senescence is a DDR mechanism that prevents the proliferation of cells with damaged DNA to avoid mitotic anomalies and inheritance of the damage over cell generations. Human WWOX gene resides within a common fragile site FRA16D that is preferentially prone to form breaks on metaphase chromosome upon replication stress. We report here that primary Wwox knockout (Wwox−/−) mouse embryonic fibroblasts (MEFs) and WWOX-knockdown human dermal fibroblasts failed to undergo replication-induced cellular senescence after multiple passages in vitro. Strikingly, by greater than 20 passages, accelerated cell cycle progression and increased apoptosis occurred in these late-passage Wwox−/− MEFs. These cells exhibited γH2AX upregulation and microsatellite instability, indicating massive accumulation of nuclear DNA lesions. Ultraviolet radiation-induced premature senescence was also blocked by WWOX knockdown in human HEK293T cells. Mechanistically, overproduction of cytosolic reactive oxygen species caused p16Ink4a promoter hypermethylation, aberrant p53/p21Cip1/Waf1 signaling axis and accelerated p27Kip1 protein degradation, thereby leading to the failure of senescence induction in Wwox-deficient cells after serial passage in culture. We determined that significantly reduced protein stability or loss-of-function A135P/V213G mutations in the DNA-binding domain of p53 caused defective induction of p21Cip1/Waf1 in late-passage Wwox−/− MEFs. Treatment of N-acetyl-l-cysteine prevented downregulation of cyclin-dependent kinase inhibitors and induced senescence in Wwox−/− MEFs. Our findings support an important role for fragile WWOX gene in inducing cellular senescence for maintaining genome integrity during DDR through alleviating oxidative stress.

show abstract

Wwox Deficiency Causes Downregulation of Prosurvival ERK Signaling and Abnormal Homeostatic Responses in Mouse Skin

Cited by 6 publications

References 78 publications

Normal cells repel WWOX-negative or -dysfunctional cancer cells via WWOX cell surface epitope 286-299

Normal cells repel WWOX-negative or -dysfunctional cancer cells via WWOX cell surface epitope 286-299

Mechanistic Investigation of WWOX Function in NF-kB-Induced Skin Inflammation in Psoriasis

Loss of fragile WWOX gene leads to senescence escape and genome instability

Contact Info

Product

Resources

About