Regulation of the SUMO pathway sensitizes differentiating human endometrial stromal cells to progesterone

Jones, Michael Owen; Fusi, Luca; Higham, Jenny H.; Abdel-Hafiz, Hany A.; Horwitz, Kathryn B.; Lam, Eric W.‐F.; Brosens, Jan J.

doi:10.1073/pnas.0603002103

Cited by 103 publications

(83 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the retina, Pias3-mediated sumoylation of the transcription factor Nr2e3 converts it into a potent repressor of cone-specific gene expression, thus acting as a key mechanism for rod specification (11). Sumoylation dynamics also plays a key role in the reprogramming and differentiation of the human endometrial stromal cells (HESCs) (8). Global SUMO1 deconjugation occurred during HESC differentiation, correlating with altered E3 ligase and protease expressions (8).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Sumoylation differentially regulates Sp1 to control cell differentiation

Gong

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The mammalian small ubiquitin-like modifiers (SUMOs) are actively involved in regulating differentiation of different cell types. However, the functional differences between SUMO isoforms and their mechanisms of action remain largely unknown. Using the ocular lens as a model system, we demonstrate that different SUMOs display distinct functions in regulating differentiation of epithelial cells into fiber cells. During lens differentiation, SUMO1 and SUMO2/3 displayed different expression, localization, and targets, suggesting differential functions. Indeed, overexpression of SUMO2/3, but not SUMO1, inhibited basic (b) FGF-induced cell differentiation. In contrast, knockdown of SUMO1, but not SUMO2/3, also inhibited bFGF action. Mechanistically, specificity protein 1 (Sp1), a major transcription factor that controls expression of lens-specific genes such as β-crystallins, was positively regulated by SUMO1 but negatively regulated by SUMO2. SUMO2 was found to inhibit Sp1 functions through several mechanisms: sumoylating it at K683 to attenuate DNA binding, and at K16 to increase its turnover. SUMO2 also interfered with the interaction between Sp1 and the coactivator, p300, and recruited a repressor, Sp3 to β-crystallin gene promoters, to negatively regulate their expression. Thus, stable SUMO1, but diminishing SUMO2/3, during lens development is necessary for normal lens differentiation. In support of this conclusion, SUMO1 and Sp1 formed complexes during early and later stages of lens development. In contrast, an interaction between SUMO2/3 and Sp1 was detected only during the initial lens vesicle stage. Together, our results establish distinct roles of different SUMO isoforms and demonstrate for the first time, to our knowledge, that Sp1 acts as a major transcription factor target for SUMO control of cell differentiation.transcription regulation | eye development | crystallin gene expression T he conjugation of small ubiquitin-like modifiers (SUMOs) to protein substrates (named sumoylation) is a critical posttranslational modification with diverse cellular functions (1). Three major SUMO isoforms (SUMO1, -2, and -3) were identified in vertebrates. Although the mature SUMO2 and SUMO3 share a very high level of sequence identity (97%) and cannot be immunologically discriminated (thus referred to as SUMO2/3), they significantly differ from SUMO1, with only 45% identity (2, 3). Recent studies using proteomics revealed that SUMO1 and SUMO2/3 can be targeted to both distinct and overlapping sets of substrates (4). However, whether SUMO1 and SUMO2/3 have redundant or different functions in vivo is not clear because inconsistent results have been reported in SUMO1 knockout mice (5, 6). SUMO conjugation is executed by three enzymes. The activating enzyme E1, a heterodimer of SAE1 and SAE2, transfers SUMO to the single E2-conjugating enzyme Ubc9, which either sumoylates the substrate alone, or cofunctions with different E3 ligases. Sumoylation is highly dynamic and can be rapidly reverted by sentrin-specific proteases (SE...

show abstract

Section: Discussionmentioning

confidence: 99%

“…Sumoylation is highly dynamic and can be rapidly reverted by sentrin-specific proteases (SENPs) (7). Functionally, it regulates many cellular processes, including cell differentiation (8)(9)(10)(11). In ocular tissues, sumoylation helps to determine the differentiation of cone versus rod photoreceptors (11).…”

mentioning

confidence: 99%

Sumoylation differentially regulates Sp1 to control cell differentiation

Gong

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Sumoylation often confers repressive properties. Intriguingly, cAMP signaling in ESCs alters the expression of many SUMO enzymes, resulting in a gradual loss of PR-A sumoylation and increased PR activity [64].…”

Section: Downstream Events Of Camp Signalingmentioning

confidence: 99%

Molecular and Cellular Mechanisms for Differentiation and Regeneration of the Uterine Endometrium

2008

View full text Add to dashboard Cite

Abstract. The human endometrium undergoes cyclical changes including proliferation, differentiation, tissue breakdown, and shedding (menstruation) throughout a woman's reproductive life. The postovulatory rise in ovarian progesterone induces profound remodeling and differentiation of the estradiol-primed endometrium. This change, termed decidualization, is crucial for embryo implantation and maintenance of the pregnancy. To date, activation and crosstalk of cAMP-and progesterone-mediated signaling pathways have emerged as key cellular events to drive integrated changes at both the transcriptome and the proteome levels. This results in the induction and maintenance of the decidual phenotype and function. Our recent series of studies highlights the critical role of SRC kinase activation (v-src sarcoma viral oncogene homolog) and STAT5 (signal transducer and activator of transcription 5) phosphorylation in decidualization. After separation of the functional layer of the differentiated endometrium that follows progesterone withdrawal, i.e., menstruation, the basal layer of the endometrium, under the influence of estradiol, regrows and initiates a unique form of angiogenesis and regenerates a new functional layer. The molecular and cellular mechanisms for this process remain elusive, mainly because of difficulties in reproducing menstrual tissue breakdown, shedding, and subsequent tissue regeneration in vitro. We have recently developed a "humanized" mouse model in which a functional human endometrium is reconstituted. It may be used as an in vivo experimental tool for the study of endometrial angiogenesis and regeneration. This model may also be used to identify and test new therapeutic strategies for endometriosis, endometrial cancer, implantation failure, and infertility related to endometrial dysfunction.

show abstract

“…Ca 2+ induced the transcriptional activation of the genes encoding several components of the sumoylation system, including SAE1/SAE2, Ubc9, SUMO2/3, and PIASx. In human endometrial stromal cells, cAMP and progesterone signaling induced significant changes in the expression of PIAS SUMO E3 ligases and SENPs [14]. In addition, hypoxia can induce the expression of SUMO-1 [15] and an RWD-containing sumoylation enhancer (RSUME) that functions to promote protein sumoylation (see the next section for details) [16].…”

Section: Regulation Of the Expression Of The Sumoylation Systemmentioning

confidence: 99%

Regulation of the sumoylation system in gene expression

Liu

Shuai

2008

Current Opinion in Cell Biology

View full text Add to dashboard Cite

SummaryProtein sumoylation has emerged as an important regulatory mechanism for the transcriptional machinery. Sumoylation is a highly dynamic process that is regulated in response to cellular stimuli or pathogenic challenges. Altered activity of the SUMO conjugation system is associated with human cancers and inflammation. Thus, understanding the regulation of protein sumoylation is important for the design of SUMO-based therapeutic strategies for the treatment of human diseases. Recent studies indicate that the sumoylation system can be regulated through multiple mechanisms, including the regulation of the expression of various components of the sumoylation pathway, and the modulation of the activity of SUMO enzymes. In addition, extracellular stimuli can signal to the nucleus to trigger the rapid promoter recruitment of SUMO E3 ligases, resulting in the immediate repression of transcription. Finally, the sumoylation system can also be regulated through crosstalk with other posttranslational modifications, including phosphorylation, ubiquitination, and acetylation.

show abstract

Regulation of the SUMO pathway sensitizes differentiating human endometrial stromal cells to progesterone

Cited by 103 publications

References 53 publications

Sumoylation differentially regulates Sp1 to control cell differentiation

Sumoylation differentially regulates Sp1 to control cell differentiation

Molecular and Cellular Mechanisms for Differentiation and Regeneration of the Uterine Endometrium

Regulation of the sumoylation system in gene expression

Contact Info

Product

Resources

About