SPOP Regulates Endometrial Stromal Cell Decidualization in Mice

Liu, Na; Liu, Xin; Yu, Qi; Ding, Yubin; He, Junlin; Gao, Rufei; Wang, Yingxiong; Liu, Xueqing

doi:10.1177/1933719116648215

Cited by 6 publications

(7 citation statements)

References 45 publications

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“…Using a similar approach that allows for the targeted ablation of SPOP in cells which express PGR, we demonstrate the importance of uterine SPOP for embryo implantation and endometrial decidualization. By revealing a critical role for SPOP in hormone-dependent endometrial decidualization, we provide essential in vivo support for recent in vitro studies [47] that report a pivotal involvement for murine SPOP in endometrial stromal cell decidualization in culture.…”

Section: Discussionsupporting

confidence: 56%

Uterine function in the mouse requires speckle-type poz protein†

Long

Szwarc

et al. 2018

Biology of Reproduction

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Speckle-type poz protein (SPOP) is an E3-ubiquitin ligase adaptor for turnover of a diverse number of proteins involved in key cellular processes such as chromatin remodeling, transcriptional regulation, and cell signaling. Genomic analysis revealed that SPOP somatic mutations are found in a subset of endometrial cancers, suggesting that these mutations act as oncogenic drivers of this gynecologic malignancy. These studies also raise the question as to the role of wild-type SPOP in normal uterine function. To address this question, we generated a mouse model (Spopd/d) in which SPOP is ablated in uterine cells that express the PGR. Fertility studies demonstrated that SPOP is required for embryo implantation and for endometrial decidualization. Molecular analysis revealed that expression levels of the PGR at the protein and transcript level are significantly reduced in the Spopd/d uterus. While this result was unexpected, this finding explains in part the dysfunctional phenotype of the Spopd/d uterus. Moderate increased levels of the ESR1, GATA2, and SRC2 were detected in the Spopd/d uterus, suggesting that SPOP is required to maintain the proteome for normal uterine function. With age, the Spopd/d endometrium exhibits large glandular cysts with foci of epithelial proliferation, further supporting a role for SPOP in maintaining a healthy uterus. Collectively, studies on the Spopd/d mouse support an important role for SPOP in normal uterine function and suggest that this mouse model may prove useful to study the role of SPOP-loss-of-function mutations in the etiopathogenesis of endometrial cancer.

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Section: Discussionsupporting

confidence: 56%

Uterine function in the mouse requires speckle-type poz protein†

Long

Szwarc

et al. 2018

Biology of Reproduction

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“…Moreover, the Cul3/SPOP/Gli3 and Cul3/SPOP/PDX1 axes promote proper skeletal development and insulin signaling by pancreatic β cells [177,178]. The stability of SPOP is essential to normalize decidualization of endometrial stromal cells in mice, however little is known as to the molecular mechanism [179]. Taken together, these results highlight key molecular pathways regulated by SPOP-mediated ubiquitination.…”

Section: Physiological and Pathological Functions Of Spop: A Regulatomentioning

confidence: 95%

“…Tumor suppressor in gastric cancer [210] Urological system ) and xenografts in nude mouse) [181,196] 2 Tumor promoter in ccRCC (Xenografts in nude mouse) [223] 1 Tumor suppressor in prostate cancer [29] 2 Tumor promoter in ccRCC [223] Gynecological system Physiology Normalizing decidualization of endometrial stromal cells in mice [179] Normalizing decidualization of endometrial stromal cells [179] Tumorigenesis Tumor suppressor in breast cancer (Xenografts in nude mouse) [166] 1 Tumor suppressor in ovarian cancer cells [201] 2 Tumor suppressor in breast cancer cells [203] 3 Tumor suppressor in endometrial cancer cells [205] Musculoskeletal Compounds that directly target Cullin 3-based E3 ligases.…”

Section: Klhl21mentioning

confidence: 99%

Functional analysis of Cullin 3 E3 ligases in tumorigenesis

Cheng

Guo

Wang

et al. 2018

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Cullin 3-RING ligases (CRL3) play pivotal roles in the regulation of various physiological and pathological processes, including neoplastic events. The substrate adaptors of CRL3 typically contain a BTB domain that mediates the interaction between Cullin 3 and target substrates to promote their ubiquitination and subsequent degradation. The biological implications of CRL3 adaptor proteins have been well described where they have been found to play a role as either an oncogene, tumor suppressor, or can mediate either of these effects in a context-dependent manner. Among the extensively studied CRL3-based E3 ligases, the role of the adaptor protein SPOP (speckle type BTB/POZ protein) in tumorigenesis appears to be tissue or cellular context dependent. Specifically, SPOP acts as a tumor suppressor via destabilizing downstream oncoproteins in many malignancies, especially in prostate cancer. However, SPOP has largely an oncogenic role in kidney cancer. Keap1, another well-characterized CRL3 adaptor protein, likely serves as a tumor suppressor within diverse malignancies, mainly due to its specific turnover of its downstream oncogenic substrate, NRF2 (nuclear factor erythroid 2-related factor 2). In accordance with the physiological role the various CRL3 adaptors exhibit, several pharmacological agents have been developed to disrupt its E3 ligase activity, therefore blocking its potential oncogenic activity to mitigate tumorigenesis.

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“…Recently, a SPOP −/− mouse model was generated and exhibited an infertility phenotype with a reduction in progesterone receptors (PRs) in the uterus [114]. In addition, based on artificially induced decidualization and steroid hormoneprocessing mouse models, researchers have demonstrated that SPOP is required for embryonic implantation and for endometrial decidualization [115]. Collectively, these findings support a crucial role for SPOP in regulating normal uterine function.…”

Section: Endometrial Cancer (Ec)mentioning

confidence: 96%

The emerging role of SPOP protein in tumorigenesis and cancer therapy

Song

Pan

et al. 2020

Mol Cancer

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The nuclear speckle-type pox virus and zinc finger (POZ) protein (SPOP), a representative substrate-recognition subunit of the cullin-RING E3 ligase, has been characterized to play a dual role in tumorigenesis and cancer progression. Numerous studies have determined that SPOP suppresses tumorigenesis in a variety of human malignancies such as prostate, lung, colon, gastric, and liver cancers. However, several studies revealed that SPOP exhibited oncogenic function in kidney cancer, suggesting that SPOP could exert its biological function in a cancer type-specific manner. The role of SPOP in thyroid, cervical, ovarian, bone and neurologic cancers has yet to be determined. In this review article, we describe the structure and regulation of SPOP in human cancer. Moreover, we highlight the critical role of SPOP in tumorigenesis based on three major categories: physiological evidence (animal models), pathological evidence (human cancer specimens) and biochemical evidence (downstream ubiquitin substrates). Furthermore, we note that SPOP could be a promising therapeutic target for cancer treatment.

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SPOP Regulates Endometrial Stromal Cell Decidualization in Mice

Cited by 6 publications

References 45 publications

Uterine function in the mouse requires speckle-type poz protein†

Uterine function in the mouse requires speckle-type poz protein†

Functional analysis of Cullin 3 E3 ligases in tumorigenesis

The emerging role of SPOP protein in tumorigenesis and cancer therapy

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