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General Comment |
NUPR1 Silencing Induces Autophagy-Mediated Apoptosis in Multiple Myeloma Cells Through the PI3K/AKT/mTOR Pathway. Li A et al. (2020) Nuclear protein 1 (NUPR1) is a stress-related small molecule and plays important roles in various tumors, including multiple myeloma (MM). Autophagy is essential for maintaining cellular homoeostasis in response to stress and, together with apoptosis, determines cell fate. Previous studies indicate that NUPR1 is involved in cancer progression of MM, but the underlying mechanisms have not been elucidated. In this study, we confirmed that NUPR1 and basal autophagy markers were highly expressed in the bone marrow of MM patients. The overexpression of NUPR1 was correlated with staging (both by Revised International Staging System [RISS] and Durie-Salmon [D-S] Staging System), levels of hemoglobin and calcium, and bone marrow plasma cell ratio in the MM patients. NUPR1 silencing reduced autophagy activities and induced apoptosis in U266 and RPMI 8226. We further observed a decrease in NUPR1 silencing-induced apoptosis in the presence of rapamycin, while an increase in apoptosis after chloroquine and 3-methyladenine treatment. Analysis of the mechanism indicated that PI3K/AKT/mTOR pathway was involved in autophagy-mediated apoptosis upon NUPR1 knockdown. In summary, our results demonstrate that NUPR1 silencing suppresses autophagy activities and induces autophagy-mediated apoptosis in MM cells through the PI3K/AKT/mTOR pathway, which exhibits potential as a treatment strategy for MM.//////////////////
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Mutations |
2 mutations
Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Array Comparative Genomic Hybridization Profiling Analysis Reveals Deoxyribonucleic Acid Copy Number Variations Associated with Premature Ovarian Failure. Aboura A et al. Introduction: Premature ovarian failure (POF) is defined by amenorrhea of at least 4- to 6-month duration, occurring before 40 yr of age, with two FSH levels in the postmenopausal range. Its etiology remains unknown in more than 80% of cases. Standard karyotypes, having a resolution of 5-10 Mb, have identified critical chromosomal regions, mainly located on the long arm of the X chromosome. Array comparative genomic hybridization (a-CGH) analysis is able to detect submicroscopic chromosomal rearrangements with a higher genomic resolution. We searched for copy number variations (CNVs), using a-CGH analysis with a resolution of approximately 0.7 Mb, in a cohort of patients with POF. Patients and Methods: We prospectively included 99 women. Our study included a conventional karyotype and DNA microarrays comprising 4500 bacterial artificial chromosome clones spread on the entire genome. Results: Thirty-one CNVs have been observed, three on the X chromosome and 28 on autosomal chromosomes. Data have been compared to control populations obtained from the Database of Genomic Variants (http://projects.tcag.ca/variation). Eight statistically significantly different CNVs have been identified in chromosomal regions 1p21.1, 5p14.3, 5q13.2, 6p25.3, 14q32.33, 16p11.2, 17q12, and Xq28. Conclusion: We report the first study of CNV analysis in a large cohort of Caucasian POF patients. In the eight statistically significant CNVs we report, we found five genes involved in reproduction, thus representing potential candidate genes in POF. The current study along with emerging information regarding CNVs, as well as data on their potential association with human diseases, emphasizes the importance of assessing CNVs in cohorts of POF women.
Species: mouse
Mutation name:
type: null mutation
fertility: subfertile
Comment: Loss of the protein NUPR1 (p8) leads to delayed LHB expression, delayed ovarian maturation, and testicular development of a sertoli-cell-only syndrome-like phenotype in mice. Million Passe CM et al. (2008) The high mobility group factor NUPR1, also known as p8 and com1, plays a role in temporal expression of the beta subunit of luteinizing hormone, LHB, during gonadotroph development. At Embryonic Day (e) 16.5, LHB is detectable in wild-type (Nupr1(+/+)) but not Nupr1 knockout (Nupr1(-/-)) mice. LHB is initiated by e17.5 in Nupr1(-/-) mice, and expression is fully recovered by Postnatal Day (p) 2. Factors indicative of pituitary maturation, GATA2, CGA, and TSH, are not differentially expressed in Nupr1(-/-) and Nupr1(+/+) embryos at e17.5. Therefore, the delay in LHB expression does not appear to result from delayed pituitary development. In addition, the role of NUPR1 in gonadotropin expression appears specific for LHB, as no difference in FSHB is observed in Nupr1(-/-) and Nupr1(+/+) embryos. The gonads are also impacted by the absence of NUPR1. Ovaries of female Nupr1(-/-) mice lack corpora lutea (CL) at 8 wk, an age at which CL are present in all Nupr1(+/+) littermates. Sexual maturity is recovered by 11 wk in Nupr1(-/-) mice. Conversely, the testes of Nupr1(-/-) males appear normal through 8 mo of age. By 10 mo, however, these mice develop a condition in which a significant number of seminiferous tubules lack germ cells, an abnormality reminiscent of human Sertoli-cell-only syndrome. NUPR1 is undetectable in Nupr1(+/+) gonadotrophs by p2 and remains absent in adulthood, but quantitative PCR analysis indicates Nupr1(+/+) adult ovaries and testes express Nupr1 mRNA. Therefore, the ovarian and testicular phenotypes may be due to the loss of NUPR1 directly at the gonads.//////////////////
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