<scp>UNC</scp>119 is a binding partner of tumor suppressor Ras‐association domain family 6 and induces apoptosis and cell cycle arrest by <scp>MDM</scp>2 and p53

Iwasa, Hiroaki; Sarkar, Aradhan; Shimizu, Takanobu; Sawada, Takeru; Hossain, Sabbir; Xu, Xiaoyin; Maruyama, Junichi; Arimoto-Matsuzaki, Kyoko; Withanage, Kanchanamala; Nakagawa, Kentaro; Kurihara, Hidetake; Kuroyanagi, Hidehito; Hata, Yoshinobu

doi:10.1111/cas.13706

Cited by 4 publications

(16 citation statements)

References 31 publications

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“…As the interaction with UNC119Aa was weaker than that with UNC119Ab, we focused on UNC119Ab. UNC119B, which was previously demonstrated not to bind RASSF6, interacted with KRASB G12V (22). Therefore, it is unlikely that RASSF6 is involved in the interaction between KRASB G12V and UNC119A.…”

Section: Unc119a Interacts With Krasmentioning

confidence: 80%

“…We previously reported that UNC119A promotes the binding of RASSF6 to MDM2 (22). We also reported that the RA domain of RASSF6 binds to MDM2 and triggers apoptosis by stabilizing p53 (32).…”

Section: Unc119ab Promotes the Binding Of Rassf6 To Mdm2 Via Krasmentioning

confidence: 87%

“…A small molecule that interferes with the interaction between UNC119A and SRC has attracted attention as a potential anticancer drug (21). However, in certain cancers, a low expression of UNC119A is associated with poor patient prognosis (22). We identified UNC119A as a binding protein of RASSF6, one of the members of tumor suppressor RASSF proteins (22).…”

mentioning

confidence: 96%

“…RASSF6 also has a coiled-coil motif, named the SARAH domain, and interacts with mammalian Ste20-like kinases, the core kinases of the tumor suppressor Hippo pathway (24). In a previous study, we revealed that UNC119A promotes the binding of RASSF6 to MDM2, inhibits the MDM2-mediated p53 degradation, and functions as a tumor suppressor (22). In this study, we investigated the implication of RAS in the UNC119A-RASSF6-MDM2-p53 axis.…”

mentioning

confidence: 97%

“…However, in certain cancers, a low expression of UNC119A is associated with poor patient prognosis (22). We identified UNC119A as a binding protein of RASSF6, one of the members of tumor suppressor RASSF proteins (22). RASSF6 has a Ras association (RA) domain, binds the GTP-bound form of RAS, and is involved in RAS-mediated apoptosis and senescence (23).…”

mentioning

confidence: 99%

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The RAS-interacting chaperone UNC119 drives the RASSF6–MDM2–p53 axis and antagonizes RAS-mediated malignant transformation

Shimizu

Nakamura

Inaba

et al. 2020

Journal of Biological Chemistry

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The gene encoding the proto-oncogene GTPase RAS is frequently mutated in human cancers. Mutated RAS proteins trigger antiapoptotic and cell proliferative signals and lead to oncogenesis. However, RAS also induces apoptosis and senescence, which may contribute to the eradication of cells with RAS mutations. We previously reported that Ras association domain family member 6 (RASSF6) binds MDM2 proto-oncogene (MDM2) and stabilizes the tumor suppressor p53 and that the active form of KRAS promotes the interaction between RASSF6 and MDM2. We also reported that Unc-119 lipid-binding chaperone (UNC119A), a chaperone of myristoylated proteins, interacts with RASSF6 and regulates RASSF6-mediated apoptosis. In this study, using several human cancer cell lines, quantitative RT-PCR, RNAi-based gene silencing, and immunoprecipitation/-fluorescence and cell biology assays, we report that UNC119 interacts with the active form of KRAS and that the C-terminal modification of KRAS is required for this interaction. We also noted that the hydrophobic pocket of UNC119, which binds the myristoylated peptides, is not involved in the interaction. We observed that UNC119 promotes the binding of KRAS to RASSF6, enhances the interaction between RASSF6 and MDM2, and induces apoptosis. Conversely, UNC119 silencing promoted soft agar colony formation, migration, and invasiveness in KRAS-mutated cancer cells. We conclude that UNC119 promotes KRAS-mediated p53-dependent apoptosis via RASSF6 and may play a tumor-suppressive role in cells with KRAS mutations.

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Section: Unc119a Interacts With Krasmentioning

confidence: 80%

Section: Unc119ab Promotes the Binding Of Rassf6 To Mdm2 Via Krasmentioning

confidence: 87%

mentioning

confidence: 96%

mentioning

confidence: 97%

mentioning

confidence: 99%

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The RAS-interacting chaperone UNC119 drives the RASSF6–MDM2–p53 axis and antagonizes RAS-mediated malignant transformation

Shimizu

Nakamura

Inaba

et al. 2020

Journal of Biological Chemistry

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DNA Damage Triggers the Nuclear Accumulation of RASSF6 Tumor Suppressor Protein via CDK9 and BAF53 To Regulate p53 Target Gene Transcription

Kuleape

Hossain

Sinclear

et al. 2022

Molecular and Cellular Biology

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RASSF6, a member of the tumor suppressor Ras-association domain family (RASSF) proteins, regulates cell cycle arrest and apoptosis via p53 and plays a tumor suppressor role. We previously reported that RASSF6 blocks MDM2-mediated p53 degradation and enhances p53 expression. In this study, we demonstrated that RASSF6 has nuclear-localization and nuclear-export signals and that DNA damage triggers the nuclear accumulation of RASSF6. We found that RASSF6 directly binds to BAF53, the component of SWI/SNF complex. DNA damage induces CDK9-mediated phosphorylation of BAF53, which enhances the interaction with RASSF6 and increases the amount of RASSF6 in the nucleus. Subsequently, RASSF6 augments the interaction between BAF53 and BAF60a, another component of SWI/SNF complex, and further promotes the interaction of BAF53 and BAF60a with p53. BAF53 silencing or BAF60a silencing attenuates RASSF6-mediated p53-target gene transcription and apoptosis. Thus, RASSF6 is involved in the regulation of DNA damage-induced complex formation including CDK9, BAF53, BAF60a, and p53.

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Knockdown of PKM2 enhances radiosensitivity of cervical cancer cells

et al. 2019

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Background: Pyruvate kinase isozyme type M2 (PKM2) catalyzes the final step in glycolysis and has been found to be up-regulated in multiple human malignancies. However, whether PKM2 regulates the radiosensitivity of human cervical cancer (CC) remains unknown. Methods: The expression of PKM2 in 94 patients with CC in the complete response (CR) and noncomplete response (nCR) groups, was evaluated by immunohistochemistry. The effect of PKM2 inhibition on radiosensitivity, the cell cycle, DNA damage, and apoptosis was evaluated by immunofluorescence analysis, colony formation assay, flow cytometry analysis and Western blotting. Results: PKM2 expression was more highly expressed in the nCR group than that in CR group and PKM2 expression was enhanced in CC cells after ionizing radiation (IR). In addition, knockdown of PKM2 combined with IR significantly reduced cell growth, promoted apoptosis, and enhanced radiosensitivity. Additionally, knockdown of PKM2 with IR resulted in increased phosphorylation of DNA repair checkpoint proteins (ATM) and phosphorylated-H2AX. Moreover, knockdown of PKM2 combined with IR significantly increased the expression of cleaved caspase 3 and caspase 9, whereas Bcl2 expression was suppressed. Furthermore, knockdown of PKM2 combined with IR markedly reduced the expression of several cancer stem cell biomarkers in vitro, including NANOG, OCT4, SOX2, and Bmi1. Conclusions: The results of our study suggests that PKM2 might be involved in mediating CC radiosensitivity and is identified as a potentially important target to enhance radiosensitivity in patients with CC.

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UNC119 is a binding partner of tumor suppressor Ras‐association domain family 6 and induces apoptosis and cell cycle arrest by MDM2 and p53

Cited by 4 publications

References 31 publications

The RAS-interacting chaperone UNC119 drives the RASSF6–MDM2–p53 axis and antagonizes RAS-mediated malignant transformation

The RAS-interacting chaperone UNC119 drives the RASSF6–MDM2–p53 axis and antagonizes RAS-mediated malignant transformation

DNA Damage Triggers the Nuclear Accumulation of RASSF6 Tumor Suppressor Protein via CDK9 and BAF53 To Regulate p53 Target Gene Transcription

Knockdown of PKM2 enhances radiosensitivity of cervical cancer cells

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