TSG101 (tumor susceptibility gene 101) is a multi-domain protein known to act in the cell nucleus, cytoplasm, and periplasmic membrane. Remarkably, TSG101, whose location within cells varies with the stage of the cell cycle, affects biological events as diverse as cell growth and proliferation, gene expression, cytokinesis, and endosomal trafficking. The functions of TSG101 additionally are recruited for viral and microvesicle budding and for intracellular survival of invading bacteria. Here we report that the TSG101 protein also interacts with and down-regulates the promoter of the p21 (CIP1/WAF1) tumor suppressor gene, and identify a p21 locus and TSG101 domains that mediate this interaction. TSG101 deficiency in Saos-2 human osteosarcoma cells was accompanied by an increased abundance of p21 mRNA and protein and the retardation of cell proliferation. A cis-acting element in the p21 promoter that interacts with TSG101 and is required for promoter repression was located using chromatin immunoprecipitation (ChIP) analysis and p21-driven luciferase reporter gene expression, respectively. Additional analysis of TSG101 deletion mutants lacking specific domains established the role of the central TSG101 domains in binding to the p21 promoter and demonstrated the additional essentiality of the TSG101 C-terminal steadiness box (SB) in the repression of p21 promoter activity. Neither binding of TSG101 to the p21 promoter nor repression of this promoter required the TSG101 N-terminal UEV domain, which mediates the ubiquitin-recognition functions of TSG101 and its actions as a member of ESCRT endocytic trafficking complexes, indicating that regulation of the p21 promoter by TSG101 is independent of its role in such trafficking.
PMID 24244542 24244542 DOI 10.1371/journal.pone.0079674 10.1371/journal.pone.0079674
Cite this article
Lin, Y. S., Chen, Y. J., Cohen, S., & Cheng, T. (2013). Identification of TSG101 functional domains and p21 loci required for TSG101-mediated p21 gene regulation. PloS one, 8(11), e79674. https://doi.org/10.1371/journal.pone.0079674
Lin YS, Chen YJ, Cohen S, Cheng T. Identification of TSG101 functional domains and p21 loci required for TSG101-mediated p21 gene regulation. PLoS One. 2013;8(11):e79674. doi:10.1371/journal.pone.0079674
Lin, Yu Shiuan, et al. "Identification of TSG101 functional domains and p21 loci required for TSG101-mediated p21 gene regulation." PloS one, vol. 8, no. 11, 2013, pp. e79674.
Keywords
Cyclin-Dependent Kinase Inhibitor P21, DNA-Binding Proteins, Endosomal Sorting Complexes Required for Transport, Transcription Factors, Tsg101 Protein
The number of sperm that reaches the oocytes in mammalian species is limited. In mice, 8-10 oocytes are ovulated, a similar number of sperm reaches the oocytes, and nearly all oocytes are fertilized via natural mating. Meanwhile, our improved superovulation technique (ultrasuperovulation: administration of inhibin antiserum and equine chorionic gonadotropin [IASe]) produced 100 oocytes from a single female C57BL/6 mouse but resulted in only approximately 20 fertilized oocytes via mating. We hypothesized that sperm shortage in the ampulla might cause this low fertilization rate. Mice were mated in the proestrus stage or after hormone injection, but ovulation timing was not considered. In clinical application, the rhythm method supports fertilization by testing the ovulation period and synchronizing the ovulation and copulation timings. Therefore, this study examined the effects of ovulation and copulation timings on in vivo fertilization in female mice with IASe. Synchronization of the ovulation and copulation timings increased fertilization efficiency in female mice with ultrasuperovulation. The number of embryos obtained post ovulation was three times higher than that obtained pre ovulation. This study suggests that synchronized ovulation and copulation timings improve the efficiency of in vivo fertilization in IASe-treated female mice. This technique can be used to produce genetically modified mice and develop technologies for infertility treatment.
Aside from human papillomavirus (HPV), the role of other risk factors in cervical cancer such as age, education, parity, sexual partners, smoking and human immunodeficiency virus (HIV) have been described but never ranked in order of priority. We evaluated the contribution of several known lifestyle co-risk factors for cervical cancer among black South African women. We used participant data from the Johannesburg Cancer Study, a case-control study of women recruited mainly at Charlotte Maxeke Johannesburg Academic Hospital between 1995 and 2016. A total of 3,450 women in the study had invasive cervical cancers, 95% of which were squamous cell carcinoma. Controls were 5,709 women with cancers unrelated to exposures of interest. Unconditional logistic regression models were used to calculate adjusted odds ratios (ORadj) and 95% confidence intervals (CI). We ranked these risk factors by their population attributable fractions (PAF), which take the local prevalence of exposure among the cases and risk into account. Cervical cancer in decreasing order of priority was associated with (1) being HIV positive (ORadj = 2.83, 95% CI = 2.53-3.14, PAF = 17.6%), (2) lower educational attainment (ORadj = 1.60, 95% CI = 1.44-1.77, PAF = 16.2%), (3) higher parity (3+ children vs 2-1 children (ORadj = 1.25, 95% CI = 1.07-1.46, PAF = 12.6%), (4) hormonal contraceptive use (ORadj = 1.48, 95% CI = 1.24-1.77, PAF = 8.9%), (5) heavy alcohol consumption (ORadj = 1.44, 95% CI = 1.15-1.81, PAF = 5.6%), (6) current smoking (ORadj = 1.64, 95% CI = 1.41-1.91, PAF = 5.1%), and (7) rural residence (ORadj = 1.60, 95% CI = 1.44-1.77, PAF = 4.4%). This rank order of risks could be used to target educational messaging and appropriate interventions for cervical cancer prevention in South African women.
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