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PubMed2025

GWAS of CRP response to statins further supports the role of APOE in statin response: A GIST consortium study.

Statins are first-line treatments in the primary and secondary prevention of cardiovascular disease. Clinical studies show statins act independently of lipid-lowering mechanisms to decrease C-reactive protein (CRP), an inflammation marker. We aim to elucidate genetic loci associated with CRP statin response. CRP statin response is the change in log-CRP between off-treatment and on-treatment measurements. Cohort-level Genome-Wide Association Studies (GWAS) of CRP response were performed using 1000 Genomes imputed data, testing ∼10 million common genetic variants. GWAS meta-analysis combined results from seven cohorts and clinical trials totalling 14,070 statin-treated individuals of European ancestry within the GIST consortium. Secondary analyses included statin-by-placebo interaction analyses, and lookups in African ancestry cohorts. Our GWAS identified two genome-wide significant (P < 5e-8) loci: APOE and HNF1A for CRP statin response corrected for baseline CRP. The missense lead variant rs429358 at APOE, contributing to the APOE-E4 haplotype, is a risk locus for dyslipidaemia, Alzheimer's and coronary artery disease (CAD). The HNF1A locus is associated with diabetes, cholesterol levels, and CAD. Both loci are also associated with baseline CRP levels, and neither locus achieved a significant (P < 0.05) result from the statin v. placebo interaction meta-analysis using randomized clinical trial data. However, the interaction result (P-int=0.09) for APOE was suggestive and possibly underpowered. The APOE-E4 signal may therefore be associated with both CRP and LDL-cholesterol statin response. Combined with suggestions in the literature that APOE also leads to differential statin benefit in Alzheimer's, the APOE locus warrants further investigation for potential genetic effects on healthcare with statin treatment.

Humans↗

PubMed1979

Synthesis of all the stereoisomers of statine (4-amino-3-hydroxy-6-methylheptanoic acid). Inhibition of pepsin activity by N-carbobenzoxy-L-valyl-L-valyl-statine derived from the four stereoisomers.

Synthesis of all four stereoisomers of the novel amino acid statine, 4-amino-3-hydroxy-6-methylheptanoic acid, found in pepstatin, a potent acid protease inhibitor, has been accomplished. Carbobenzoxy-L-valyl-L-valyl-statine tripeptides derived from all four stereoisomers have been prepared and their effect on pepsin activity is compared to that of pepstatin.

Amino Acids↗

PubMed1989

Synthesis of the novel pi-(benzyloxymethyl)-protected histidine analogue of statine. Inhibition of penicillopepsin by pepstatin-derived peptides containing different statine side-chain derivatives.

The synthesis of aspartic proteinase inhibitors derived from a new histidine side-chain analogue of statine (Sta), (3S,4S)-4-amino-3-hydroxy-5-(imidazol-4-yl)pentanoic acid (HiSta, 20), is reported. Boc-HiSta(BOM)-OMe (7) was prepared in 16% overall yield from Boc-His(pi-BOM)-OH via formation of the tetramic acid derivative 11 and stereoselective cis reduction with NaBH4 to the 4-hydroxy lactam 12. Removal of the Boc group from ester 7 (enantiomeric purity ee = 88-90%) and coupling to the tripeptide segment Iva-Val-Val-OH (13) by the DCC/HOBt preactivation method followed by hydrogenolytic removal of the pi-BOM group over Pd(OH)2 on carbon gave Iva-Val-Val-HiSta-OMe (16). This new peptide 16 is a very potent inhibitor of the fungal aspartic proteinase penicillopepsin (Ki = 4.5 x 10(-9) M) that is 10 times more active than the comparable Sta-containing inhibitor 3 and 2-3 times more potent than the new (3S,4S)-4-amino-3-hydroxy-5-phenylpentanoic acid (AHPPA) analogue 17 (Ki = 1.5 x 10(-8) M). However, compound 16, which has an imidazole residue at the P1 position, is a significantly weaker inhibitor of the enzyme than the corresponding analogues with the lysine (5) and ornithine (6) side chains at P1. Considerations that led to the synthesis of 16 and the results of the enzyme kinetics are discussed in detail.

Amino Acids↗

PubMed2022

Genetically predicted on-statin LDL response is associated with higher intracerebral haemorrhage risk.

Statins lower low-density lipoprotein cholesterol and are widely used for the prevention of atherosclerotic cardiovascular disease. Whether statin-induced low-density lipoprotein reduction increases risk of intracerebral haemorrhage has been debated for almost two decades. Here, we explored whether genetically predicted on-statin low-density lipoprotein response is associated with intracerebral haemorrhage risk using Mendelian randomization. Using genomic data from randomized trials, we derived a polygenic score from 35 single nucleotide polymorphisms of on-statin low-density lipoprotein response and tested it in the population-based UK Biobank. We extracted statin drug and dose information from primary care data on a subset of 225 195 UK Biobank participants covering a period of 29 years. We validated the effects of the genetic score on longitudinal low-density lipoprotein measurements with generalized mixed models and explored associations with incident intracerebral haemorrhage using Cox regression analysis. Statins were prescribed at least once to 75 973 (31%) of the study participants (mean 57 years, 55% females). Among statin users, mean low-density lipoprotein decreased by 3.45 mg/dl per year [95% confidence interval (CI): (-3.47, -3.42)] over follow-up. A higher genetic score of statin response [1 standard deviation (SD) increment] was associated with significant additional reductions in low-density lipoprotein levels [-0.05 mg/dl per year, (-0.07, -0.02)], showed concordant lipidomic effects on other lipid traits as statin use and was associated with a lower risk for incident myocardial infarction [hazard ratio per SD increment 0.98 95% CI (0.96, 0.99)] and peripheral artery disease [hazard ratio per SD increment 0.93 95% CI (0.87, 0.99)]. Over a 11-year follow-up period, a higher genetically predicted statin response among statin users was associated with higher intracerebral haemorrhage risk in a model adjusting for statin dose [hazard ratio per SD increment 1.16, 95% CI (1.05, 1.28)]. On the contrary, there was no association with intracerebral haemorrhage risk among statin non-users (P = 0.89). These results provide further support for the hypothesis that statin-induced low-density lipoprotein reduction may be causally associated with intracerebral haemorrhage risk. While the net benefit of statins for preventing vascular disease is well-established, these results provide insights about the personalized response to statin intake and the role of pharmacological low-density lipoprotein lowering in the pathogenesis of intracerebral haemorrhage.

Cerebral Hemorrhage↗

PubMed1990

Expression of statin, a non-proliferation-dependent nuclear protein, in the postnatal rat brain: evidence for substantial retention of neuroglial proliferative capacity with aging.

Statin is a 57 kDa protein expressed in nuclei of reversibly and irreversibly growth-arrested (Go-phase) cells. In this report, immunohistochemical localization of statin in the developing and aging rat brain was achieved using the monoclonal antibody, S-44. On postnatal day 2, post-migratory neurons in the developing cerebral cortex were statin-positive. Many statin-negative cells were observed in the lateral subependymal zone of the lateral ventricle. By postnatal day 10, most neuronal nuclei were statin-positive although small numbers of statin-negative neurons were still encountered in the lateral subependymal zone and hippocampal dentate gyrus. At 3, 18 and 33 months, all neuronal nuclei surveyed were statin-positive. These results support the contention that, save for the postnatal persistence of 'germinal zones' such as the subependymal region and dentate gyrus, neuronal proliferation in the rat is largely completed by the time of birth. In striking contrast to neuronal statin expression, a significant fraction of neuroglia in both grey and white matter remains statin-negative at all ages examined. In the corpus callosum, 33.2%, 34.0% and 34.7% of glial nuclei were statin-negative at 3, 18 and 33 months, respectively. These findings indicate that: (i) even in senescent brain, the cycling (statin-negative) glial pool is substantially larger than previously surmised from S-phase labeling experiments; and (ii) during aging, the ratio of noncycling-to-cycling neuroglia remains very tightly regulated. Examination of other non-neuronal cell types revealed that most, if not all, ependymal and choroid plexus epithelial cells were statin-positive in the neonatal and adult brains in keeping with the predominantly prenatal proliferation of these tissues. Our results indicate that statin immunolabeling using the S-44 antibody is a powerful technique for the in situ identification of non-proliferating cells in the developing and aging nervous system.

Aging↗

PubMed2026

Cardioprotective glucose-lowering drugs, statins, and secondary major adverse cardiovascular events: a nationwide cohort study of individuals with type 2 diabetes and cardiovascular disease.

BACKGROUND: In type 2 diabetes, cardioprotective glucose-lowering drugs, including sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, and statins reduce the risk of secondary major adverse cardiovascular events. No trials examined the combination of these drugs as withholding statins in high-risk individuals would be unethical. We tested the hypothesis that cardioprotective glucose-lowering drug and statin combined is associated with lower risk of secondary major adverse cardiovascular events than either drug alone. METHODS: Individuals with type 2 diabetes and established cardiovascular disease from December 2012 through 2021 were identified via national Danish health registers. They were analyzed in an active comparator cohort including 15,404 individuals followed from treatment intensification with cardioprotective glucose-lowering drug or dipeptidyl peptidase-4 inhibitor and additionally in a time-varying cohort including 76,853 individuals with yearly updated treatment and covariate status. The treatment groups were: (i) no cardioprotective drug (no use of cardioprotective glucose-lowering drug or statin), (ii) cardioprotective glucose-lowering drug, (iii) statin, and (iv) cardioprotective glucose-lowering drug and statin. The primary outcome was a new major adverse cardiovascular event (myocardial infarction, stroke, or cardiovascular death). RESULTS: During mean 2.7 and 4.7 years of follow-up, 1,843 and 23,051 had major adverse cardiovascular events in the active comparator and time-varying cohorts. In the active comparator cohort, when compared to nonusers of cardioprotective glucose-lowering drug or statin, multivariable adjusted hazard ratios of major adverse cardiovascular events were 0.82 (95% confidence interval: 0.67 to 1.02) for cardioprotective glucose-lowering drug, 0.85 (0.74 to 0.97) for statin, and 0.71 (0.60 to 0.84) for cardioprotective glucose-lowering drug and statin combined. Corresponding hazard ratios in the time-varying cohort were 0.77 (0.69 to 0.86), 0.73 (0.70 to 0.75), and 0.57 (0.54 to 0.60), respectively. When restricting the active comparator cohort to individuals entering observation between 2019 and 2021 with reduced statistical power, the corresponding hazard ratios were 0.86 (0.57 to 1.31), 0.89 (0.60 to 1.30), and 0.79 (0.54 to 1.14), respectively. In both cohorts p for interaction between cardioprotective glucose-lowering drug and statin was > 0.05. CONCLUSIONS AND RELEVANCE: In individuals with type 2 diabetes and established cardiovascular disease, treatment with a cardioprotective glucose-lowering drug and statin in combination was associated with lower risk of secondary major adverse cardiovascular events than using either drug alone. This is important given the persistently suboptimal uptake of both drug classes in real-world practice. Some biases can never be completely excluded in real-world pharmacotherapy use studies such as this one, including confounding by indication, time-related or immortal time biases, and shifting standards of care, rendering causal interpretation unattainable; however, our results seemed consistent across numerous sensitivity analyses and designs.

Humans↗

PubMed1990

The relationship of expression of statin, the nuclear protein of nonproliferating cells, to the differentiation and cell cycle of astroglia in cultures and in situ.

Cells in the quiescent, nonproliferative state express a protein, statin, in their nuclei. When the cells reenter the cell cycle, statin disappears and another protein, cyclin, appears. We have examined mouse astroglia at various stages of differentiation in cultures and astroglia in adult mouse brains for the presence of statin. In cultures initiated from the neopallium of newborn mice, the glial fibrillary acidic protein (GFAP)+ stellate astrocytes were statin-negative (statin-) but cyclin-positive (cyclin+). In the same cultures, large flat cells (senescent cells) were statin+ but cyclin-. In frozen sections of the brains of adult mice and in brain smears, GFAP+ astrocytes were statin-. Neither stellate astrocytes grown in cultures for 30 or more days nor astrocytes in adult mouse brain were labeled when pulsed with bromodeoxyuridine (BudR). When astroglia were treated with dibutyrl cyclic adenosine monophosphate (dBcAMP), large stellate cells that closely resemble reactive astrocytes in situ formed. These cells were all statin+ from 11-62 days in vitro; however, reactive astrocytes in mouse neopallium, 4-50 days after a stab wound, were statin-. In colony cultures, senescent cells became statin+, whereas stellate astrocytes and their precursor cells remained statin-. These observations indicate that normal astrocytes both in cultures and in situ retain the potential to divide and probably progress through the cell cycle at a very slow rate.

Animals↗

PubMed1991

Statin immunolocalization in human brain tumors. Detection of noncycling cells using a novel marker of cell quiescence.

Surgical specimens of 35 human brain tumors were examined with a novel monoclonal antibody, S-44, immunoreactive to statin, a nuclear protein specifically expressed in quiescent (noncycling) G0-phase cells. Benign tumors typically were statin positive with labeling indices (LI) between 22% and 96%: acoustic schwannomas (n = 3, mean = 29.9 +/- 19.4%); meningiomas (n = 4, mean = 59.0 +/- 15.1%); pituitary adenomas (n = 3, mean = 79.9 +/- 28.2%), and an epidermoid cyst (41.0%). By contrast, the statin LI of 18 of 24 (75%) malignant brain tumors was less than or equal to 2%: medulloblastomas (n = 7, mean = 0.3 +/- 0.2%); anaplastic astrocytomas (n = 3, mean = 1.6 +/- 2.7%); glioblastomas (n = 10, mean = 10.3 +/- 14.4%); metastatic carcinomas (n = 3, mean = 3.0 +/- 4.6); and a germinoma (0.2%). The vascular endothelium among diverse tumors typically was statin positive. All 21 tumors with a statin LI less than 10% were malignant, and all nine tumors with a statin LI greater than 40% were benign. The statin LI of benign tumors (n = 11, mean = 55.1 +/- 26.7%) was significantly higher than that of the malignant tumors (n = 24, mean = 5.2 +/- 10.5%, P less than 0.001). The absence of statin expression is a new way to determine the malignancy of human brain tumors. The statin LI may be useful to guide the prognosis and treatment of individual patients. The mechanisms that control statin expression are important in therapy seeking to shift the proliferating, cycling cells to the quiescent, G0 compartment.

Adolescent↗

PubMed1990

Characterization of two populations of statin and the relationship of their syntheses to the state of cell proliferation.

Statin has previously been identified to be a 57-kD protein present in the nuclei of quiescent and senescent human fibroblasts, but not in their replicating counterparts (Wang, E. 1985. J. Cell Biol. 100: 545-551). In the present report we demonstrate by immunoprecipitation analysis of fractionated cellular extracts the existence of two populations of statin. The Triton X-100-soluble statin is found in replicating sparse cultures as well as in quiescent confluent cultures and quiescent serum-starved cultures of young human fibroblasts, but the Triton X-100-insoluble, nuclear envelope-localized statin is present only in the quiescent cultures. Two-dimensional gel analysis of the immunoprecipitated cellular fractions reveals that both populations of statin have an isoelectric point of 5.3. Pulse-chase experiments show that statin is synthesized as a 57-kD polypeptide and is not processed from a precursor of different molecular mass. Experiments on serum stimulation of quiescent cells show that synthesis of the Triton X-100-insoluble statin decreases rapidly during the transition from the G0 to S phase, and that this decrease is accompanied by a slower reduction in synthesis of the Triton X-100-soluble statin. These results suggest that the cellular expression of the two populations of statin may be associated with the mechanisms controlling the transition between the growing state and the quiescent state and confirm the previous finding that the Triton X-100-insoluble, nuclear envelope-localized statin could be used as a marker for cells arrested at the G0 phase of the cell cycle.

Cell Cycle Proteins↗

PubMed1991

Isoproterenol downregulation of statin-related gene expression in the rat parotid gland.

Statin, a 57 kilodalton (kDa) nuclear protein, is characteristically found in nonproliferating cells in culture as well as nondividing cells of a wide range of highly differentiated tissues. Moreover, cells in culture that are statin positive lose this statin expression when re-entering the cell-cycle traverse. In this work, statin expression was investigated in the parotid gland of untreated rats and those treated with isoproterenol (IPR), a proliferation-inducing catecholamine. Indirect immunofluorescence microscopy revealed specific nuclear staining with anti-statin monoclonal antibody (S-44) in the acinar and ducts cells of the untreated rats but significantly reduced in those induced with isoproterenol. To characterize the protein recognized by S-44, protein extracts from both tissues were immunoblotted and incubated with S-44. The antibody reacted specifically with a 48 kDa protein in the extract of the parotid glands from untreated rats while no reaction was detected in that of the proliferation-induced ones. These observations along with the result that a statin-like (S1) transcript is downregulated by isoproterenol in the parotid glands further support the notion that the disappearance of statin-related expression is associated with the IPR-induced proliferation in the rat parotid glands. The discrepancy between the apparent molecular mass of the protein identified by S-44 in nonproliferating parotid cells and that of statin originally found in fibroblasts, suggests that either a modified form of statin may be present in the parotid gland, or this 48 kDa protein may be a member of the nonproliferative statin-like family.

Animals↗

PubMed1989

A rat liver 57-kDa protein is identified to share antigenic determinants with statin, a marker for nonproliferating cells.

The nuclear protein statin, found uniquely in nonproliferating cells, has been previously identified by mouse monoclonal antibodies designated as S-30 and S-44. We report here the screening of various rat tissues for proteins cross-reacting with these antibodies. As revealed by immunoblotting, two polypeptides (mol wt 80 and 57 kDa) and a group of lower-molecular-weight proteins migrating between 34 and 38 kDa were found to react with the anti-statin antibodies. The most prominent immunoreactivity was observed with a 57-kDa protein present in rat liver. Upon further fractionation of the liver protein extract with ammonium sulfate [(NH4)2SO4] the 57-kDa protein, designated as rat liver protein 57 or RLp57, was detected independently with both anti-statin antibodies in the 30 to 60% (NH4)2SO4 fraction. In order to determine whether rat liver protein 57 is indeed specifically recognized by anti-statin antibody S-44, we used RLp57 transferred onto nitrocellulose paper as a specific substrate for the adsorption of the S-44 antibody from ascites fluid. As shown by indirect immunofluorescence microscopy the solution remaining after adsorption failed to stain human fibroblasts. The adsorbed immunoglobulin, however, upon elution revealed statin-specific nuclear staining activity on senescent fibroblasts. These findings suggest that rat liver protein 57 and the human fibroblast statin share similar antigenic determinants recognized by the statin-specific S-44 antibody. Our results indicate furthermore that the statin previously identified in fibroblasts may represent one member of a group of several antigenically related proteins detectable with specific anti-statin antibodies.

Animals↗

PubMed2026

Association Between Statin Use and Dry Eye Disease: A Systematic Review and Meta-Analysis.

TOPIC: This systematic review and meta-analysis evaluated the literature-pooled association between statins and dry eye disease (DED). CLINICAL RELEVANCE: Statins, a common treatment modality for dyslipidemia, have been proposed as a potential contributor to DED via their activity in meibomian gland epithelial cells. However, single studies show mixed evidence, and there remains an unmet clinical need to clarify whether statin exposure is associated with DED. METHODS: This review was reported in accordance with the Preferred Reporting Items for Systematic Reviews of Interventions (PRISMA) 2020 statement and was registered a priori on PROSPERO (CRD420251238004). Ovid MEDLINE, Embase, CINAHL, Web of Science, CENTRAL, and the reference lists of relevant reviews were searched from inception to November 2025 for studies reporting the association between statin use and DED. Random-effects meta-analysis using inverse-variance weighting was conducted to pool effect estimates as odds ratios with 95% confidence intervals (CIs). Study risk of bias was appraised using the ROBINS-E tool, and the certainty of the evidence was reported using the GRADE framework. RESULTS: Six observational studies were included in the meta-analysis (n = 560,821; 356,012/559,141 [63.7%] statin users). The pooled analysis revealed a significant positive association between statins and DED (odds ratio 1.09, 95% CI 1.05-1.13, P < .001), with an absolute risk difference of 10.2 more DED cases per 1000 (95% CI 5.5 more to 15.2 more). This result was derived from very low-certainty evidence given limitations in study design and serious inconsistency. Subgroup and sensitivity analyses for risk of bias (P = .123), method of outcome ascertainment (P = .737), type of effect estimate (P = .496), and leave-one-out analyses showed no evidence of effect modification and demonstrated consistent direction of association across studies. CONCLUSION: Statin use was associated with a small but statistically significant increase in DED, limited by very low-certainty evidence. Physicians should monitor for and educate patients on ocular surface symptoms in patients using statins with pre-existing DED risk factors. Future studies should use standardized DED diagnostic criteria to investigate the impact of statin dose, type, and duration to better characterize this potential association.

Humans↗

PubMed2026

HLA and non-HLA genetic analyses reveal suggestive variants associated with statin-induced liver injury.

BACKGROUND: Statins are widely prescribed for cardiovascular risk reduction and are generally well tolerated. However, they can cause drug-induced liver injury (DILI), and the genetic factors contributing to statin-DILI remain poorly understood. METHODS: HLA association and genome-wide association (GWAS) studies were conducted to identify genetic variants associated with statin-DILI. High-confidence cases (n=71) were identified from the Drug-Induced Liver Injury Network (DILIN) and compared with statin-exposed controls without liver injury (n=551) from the Indiana Biobank. Association testing was performed across ancestries and within ancestry, adjusting for age, sex, and three principal components of genotypes. Top variants were further evaluated in non-statin DILI cases and unexposed controls. In addition, we investigated the frequency of candidate variants among a comprehensive list of pharmacogenetic variants related to statins. RESULTS: HLA-DQA1*03:01 was significantly associated with increased risk of statin-DILI (OR=3.49, 95% CI 2.21-5.51, p-value=1.27×10-7), with enrichment observed across multiple ancestry groups, particularly non-Hispanic Black and Hispanic individuals. From the GWAS, three loci showed suggestive associations (p-value <5×10-06) with statin-DILI, including rs35197737 in RGS1 (OR=5.03, 95% CI 1.11-3.66, p=1.14×10-7), rs75629598 in FRMD4A (OR=4.4, 95% CI=2.33-8.12, p=3.97×10-6), and rs7658630 in the intergenic region on chromosome 4 (OR=4.86, 95% CI 2.66-8.85, p=2.68×10-7). No pharmacogenetic variants revealed statistical significance. CONCLUSION: We identified HLA and non-HLA genetic variants associated with statin DILI. Future studies with larger sample sizes should confirm these observations.

Humans↗

PubMed1992

Modulation of nuclear statin expression in rat thyroid follicle cell following administration of thyroid stimulating hormone.

This study was designed to examine the state of proliferation in the rat thyrocyte following the administration of thyroid stimulating hormone (TSH). An immunohistochemical technique involving the use of a monoclonal antibody to statin, a nonproliferation-specific nuclear antigen, was developed to measure the subpopulation of cells that have ceased to divide. Following the random assignment of young male Sprague-Dawley rats into various groups, the rats in the control group received a single intraperitoneal (i-p) injection of normal saline, whereas the experimental groups received single i-p injections of TSH at doses of 0.25, 0.50, and 1.0 IU, respectively. All rats were subsequently sacrificed in groups of three at 1, 2, 4, and 24 hours. The statin antibody label was readily identified within the follicle cell nucleus. Results revealed a statistically significant transient decrease in the mean percent statin-positive nuclei in the TSH-treated groups. The time- and dose-dependent effect of TSH was maximal at 2 hours and no longer discernible at 24 hours. A second experiment involving the chronic administration of TSH (i-p 0.25 IU twice daily) resulted in a cumulative response with a statistically significant progressive decrease in the mean percent of statin-positive nuclei at 5 and 10 days, returning to near normal values 5 days following the cessation of treatment. Determination of the nuclear optical density of the statin reaction product by image analysis techniques revealed that a single injection of TSH resulted in a rapid disappearance of the statin nuclear protein. This result suggests that the disappearance of statin in the nucleus appears to reflect the event of cells leaving the nondividing quiescent state to resume the cell cycle traverse following the administration of TSH. The disappearance of statin appears as an early nuclear event that parallels the earliest known cytoplasmic pinocytotic response to TSH in the rat thyroid follicle cell.

Animals↗

PubMed1986

Disappearance of statin, a protein marker for non-proliferating and senescent cells, following serum-stimulated cell cycle entry.

Statin, a protein of 57,000 D, is present in the nuclei of quiescent or senescent fibroblasts (Wang, E, J cell biol 100 (1985) 545), but is absent in their young replicating counterparts. Immunohistochemical survey of a variety of tissues demonstrates that the presence of statin is a marker for cells that are no longer involved in proliferation, i.e. those cells that are terminally differentiated. Statin expression was examined by immunofluorescence microscopy in serum-starved cultures whose replication had been reinitiated by raising the serum concentration from 0.5 to 10%. Prior to serum addition, more than 85% of the cells stained positively for statin. After stimulation with serum, the expression of statin disappeared rapidly within the first 12-14 h. On the other hand, an increase in the level of DNA synthesis, signifying entry into S phase, was observed initially at 18 h after serum stimulation, and reached maximal levels 6 h later. Immunoprecipitation of statin derived from cells harvested at different intervals after serum stimulation revealed that the level of statin synthesis was reduced by 4 h and was hardly detectable at 8 h. These results demonstrate that the synthesis of statin occurs primarily when cells are in a quiescent state, and declines rapidly when cells are induced to proliferate; this decline precedes the transition from G1 to S phase.

Cell Cycle Proteins↗

PubMed1992

Statin, a protein specifically present in nonproliferating cells, is a phosphoprotein and forms a complex with a 45-kilodalton serine/threonine kinase.

The protein statin is found in nuclei of nonproliferating cells. Here we report that statin is a phosphoprotein, phosphorylated at serine residues in cultured cells. During immunoprecipitation with anti-statin (S44) antibody, a 45-kDa protein co-precipitates with the 57-kDa statin. In vitro kinase assays demonstrate that the S44 immunoprecipitates can phosphorylate, besides statin, immunoglobulins, enolase, and casein, at either serine or serine/threonine residues. Kinase assays with immunoprecipitated proteins performed on casein- or enolase-impregnated gels show that these substrates are phosphorylated by the 45-kDa (p45) protein. When the S44 immunoprecipitates from human cultured fibroblasts with different in vitro life-spans were compared, the p45 kinase activity was present only in young nongrowing and senescent cells, but not in young growing ones. In other cell cultures, the kinase is detected only in protein complexes precipitated from quiescent 3T3 cells, but not from cycling 3T3 cells or from transformed human glioma (U251-4) cells. Cell fractionation studies, indicating that the phosphorylating activity of S44 immunoprecipitates correlates both qualitatively and quantitatively with the amount of statin present, provide strong evidence that in vivo statin is specifically associated with the p45 kinase. These results suggest that the nonproliferation-specific nature of statin is indeed related to the phosphorylated property of this protein and maybe contributed by the associated kinase.

3T3 Cells↗

PubMed1991

Isolation and characterization of the rat chromosomal gene for a polypeptide (pS1) antigenically related to statin.

Increasing evidence shows the existence of nonproliferation-specific gene(s) whose expression is mostly present in growth-arrested cells. One member of this gene family has been identified by previous work as a nuclear protein of 57,000 Da, termed statin. Logical extensions of statin research are to identify the genomic and cDNA clones encoding for statin and to study the regulation of statin gene expression. During the search for the statin gene, we have identified a cDNA clone and a genomic clone named S1 and S10, respectively, by screening a rat brain lambda gt11 expression library with the statin antibody and subsequently using S1 cDNA as a probe to screen a rat genomic cosmid library. Here, we report the cloning and sequencing of the S1 cDNA and S10 genomic clones. Primary sequence analyses indicate that the derived amino acid sequence of S1 shares high homology (greater than 92.6%) with human elongation factor 1 alpha (EF-1 alpha), whereas the 5'- and 3'-untranslated regions are less than 20% homologous. Despite the unusually high degree of similarity between S1 and human EF-1 alpha at the amino acid sequence level, their protein products are different and immunologically distinct. The in vitro transcription and translation product of S1 (pS1), a 49,000-Da polypeptide, reacts only with the monoclonal antibody against statin; this antibody exhibits no antigenic reaction to the EF-1 alpha protein. Northern blot analysis shows that the S1 message is most abundant in G0 phase of 3T3 mouse fibroblasts, but becomes significantly reduced in G1 and S phase cells. EF-1 alpha messages do not show such dramatic changes during cell cycle phase transition. These findings suggest that the expression of the identified S1 cDNA clone is specific for nonproliferating cells and that the in vitro translation product of the S1 cDNA is recognized by the statin antibody. Genomic Southern blots indicate that S1 cDNA is encoded by a single copy gene in the rat genome and is a unique member of the EF-1 alpha/S1 supermultigene family. DNA sequence analysis demonstrates that the rat S1 transcription unit is 12 kilobase pairs in length and contains seven introns. The organization of exons is virtually identical between S1 and human EF-1 alpha. In contrast, neither a TATA box nor a CAAT box is located in the proximal 5'-flanking regions from positions -1 to -1359 of the S1 gene, where we could expect to find the regulatory region containing the elements controlling gene expression; no evident sequence homology to the human EF-1 alpha gene is detected in this region.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗

PubMed1989

Statin, a nonproliferation-specific protein, is associated with the nuclear envelope and is heterogeneously distributed in cells leaving quiescent state.

Statin, a protein of 57,000 daltons, is present primarily in the nuclei of nonproliferating cells of terminally differentiated tissues or of in vitro aged fibroblast cultures. In young growing cells, the protein can be induced to appear in the nuclei once the cell-cycle traverse is blocked by various tissue culture manipulations, such as serum starvation; this expression, however, can be rapidly removed by addition of serum. The disappearance of statin in cells leaving the quiescent state is not uniform along the periphery of the nucleus; it can be distributed in various patterns, such as caps, nodules, patches, or irregular granules. This unusual distribution seems to suggest that preferential sites exist at the region of the nuclear envelope where statin presence may residually remain. The concentration of statin at the nuclear envelope region in cells at G0-quiescent phase is confirmed by the intense staining of fluorescent antibody at the periphery of isolated rat liver nuclei. Further examination of the isolated nuclei reveals that the protein is associated with the lamina compartment of the nuclear envelope; this is evidenced by the results of immunoblotting experiments showing statin presence in the fraction enriched for lamins A-C. Immunogold labelling studies show that the protein is located in the general area of the nuclear envelope. These results suggest that statin in G0-quiescent cells is located predominantly at the nuclear envelope region and that in this vicinity there may exist geometrically sites of statin concentration as evidenced by the heterogeneous distribution in those cells experiencing the departure from the quiescent state.

Animals↗