Black Bars Research Articles

Internal Tandem Duplication Mutation of FLT3 (FLT3/ITD) Significantly Increases Inter Chromosomal Homologous Recombination Providing a Direct Link Between Constitutive FLT3-ITD Activity and Propagation of Copy Neutral Loss of Heterozygosity (CN-LOH) in Acute Myeloid Leukaemia

The majority of patients with adult acute myeloid leukaemia (AML) that present with an apparently normal karyotype (NK-AML) are grouped together in the “intermediate” risk category and constitute 40-45% of all adult AML patients. Mutations in the FMS-like tyrosine kinase 3 (FLT3) receptor whether it is internal tandem duplication (ITD) of its juxtamembrane domain or point mutations in its kinase domain are one of the most common mutations in NK-AML. The presence of FLT3-ITD mutation in NK-AML results in a more aggressive disease, resistance to therapy and poor survival. Acquired copy neutral loss of heterozygosity (CN-LOH) also referred to as uniparental disomy (UPD) is a common phenomenon of myeloid malignancies where an oncogenic allele is duplicated on the other chromosome. The use of single nucleotide phenotype analysis (SNP-A) karyotyping detects CN-LOH in 20% and 40% of newly diagnosed and relapsed AML respectively. CN-LOH at 6p or at the FLT3 locus 13q associated with a FLT3-ITD mutation in NK-AML results in an even more aggressive disease compared to NK-AML + FLT3-ITD without CN-LOH. It has been proposed that CN-LOH is the result of a homologous recombination (HR) DNA repair event. However, the underlying mechanisms that confer CN-LOH have yet to be determined.To elucidate the mechanisms that produce CN-LOH in NK-AML we determined whether oncogenes such as FLT3-ITD have the propensity to generate CN-LOH through up-regulation of inter chromosomal (between maternal and paternal chromosomes) HR DNA repair. We have showed previously that constitutional FLT3-ITD kinase activity increased reactive oxygen species resulting in elevated double strand breaks. Moreover, FLT3-ITD mutation increases homologous recombination activity through transcriptional augmentation of HR factor, RAD51 expression.Firstly, to evaluate FLT3-ITD induced genomic instability we measured sister chromatid exchanges (SCE) that result from HR mediated chromosome cross-over. It has been shown previously in the pre-leukaemic chromosomal instability disorder, Blooms syndrome is characterised by increased SCE and an increased propensity for CN-LOH. FLT3/ITD primary AML (n=17), MOLM-13 and FLT3-ITD transfected U937 cells show a significant increase in SCE compared to WT FLT3 primary AML cells, U937 cells transfected with empty vector, (10 vs. 6 SCE per metaphase, p<0.001) (Figure 1A-B). Importantly, primary AML with CN-LOH at 13q + FLT3-ITD mutation gives significantly higher HR activity and SCE than primary AML + FLT3-ITD mutation without CN-LOH (p<0.05). Moreover, treatment of FLT3/ITD primary AML, MOLM-13 and FLT3-ITD transfected U937 cells with the FLT3 inhibitor, CEP701 and the anti-oxidant agent, N-acetyl cysteine restored SCE to levels observed for WT FLT3. Next, we investigated whether inappropriate HR activity at G0 rather than at S phase of the cell cycle could result in illegitimate HR resulting in inter chromosomal HR. Western blot studies showed that G0 primary AML with FLT3/ITD, synchronised G0 MOLM 13 and FLT3-ITD transfected U937 cells showed augmented RAD51 expression compared to non-mutated FLT3 primary AML cells, cell lines and KG-1 transfected with empty vector (Figure 1C). Lastly, we used a thymidine kinase (TK) gene mutation assay system to screen for FLT3-ITD derived CN-LOH. The human lymphoblastoid cell line, TK6 is heterozygous for TK and becomes resistant to trifluorothymidine (TFT) upon loss of the wild type TK allele on 17q. FLT3-ITD transfected TK6 cells (using 2 different expression constructs) demonstrated significantly increased mutation frequency (grey bars) and mutation ate (Black bars) and TFT resistance compared to WT FLT3 and emptor vector control transfection (p<0.001) (Figure 1D). Colony PCR of TFT resistant colonies revealed that resistance was due primarily (80%) to inter chromosomal HR at 17q in contrast to empty vector (20%) and cisplatin treated (45%) TK6 cells (Figure 1E). The findings that FLT3-ITD mutation induces increased ROS production inducing DNA double strand breaks and the concomitant increase in the rad51 dependent inter homologous recombination provide a strong proof of principle that constitutive FLT3-ITD kinase activity directly confers CN-LOH that furthers our understanding of leukaemic progression and relapse in NK-AML. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Love: A Letter To Ashley's Father

Love: A Letter To Ashley's Father

Impact of stride-coupled gaze shifts of walking blowflies on the neuronal representation of visual targets.

During locomotion animals rely heavily on visual cues gained from the environment to guide their behavior. Examples are basic behaviors like collision avoidance or the approach to a goal. The saccadic gaze strategy of flying flies, which separates translational from rotational phases of locomotion, has been suggested to facilitate the extraction of environmental information, because only image flow evoked by translational self-motion contains relevant distance information about the surrounding world. In contrast to the translational phases of flight during which gaze direction is kept largely constant, walking flies experience continuous rotational image flow that is coupled to their stride-cycle. The consequences of these self-produced image shifts for the extraction of environmental information are still unclear. To assess the impact of stride-coupled image shifts on visual information processing, we performed electrophysiological recordings from the HSE cell, a motion sensitive wide-field neuron in the blowfly visual system. This cell has been concluded to play a key role in mediating optomotor behavior, self-motion estimation and spatial information processing. We used visual stimuli that were based on the visual input experienced by walking blowflies while approaching a black vertical bar. The response of HSE to these stimuli was dominated by periodic membrane potential fluctuations evoked by stride-coupled image shifts. Nevertheless, during the approach the cell’s response contained information about the bar and its background. The response components evoked by the bar were larger than the responses to its background, especially during the last phase of the approach. However, as revealed by targeted modifications of the visual input during walking, the extraction of distance information on the basis of HSE responses is much impaired by stride-coupled retinal image shifts. Possible mechanisms that may cope with these stride-coupled responses are discussed.

Schistura andrewi, a new species of loach (Teleostei: Nemacheilidae) from Mizoram, northeastern India.

Schistura andrewi, a new species of loach, is described from a tributary of Kaladan River in Mizoram, northeastern India. It is distinguished from its congeners in having the following combination of characters: long axillary pelvic lobe; complete lateral line with 82-95 pores; 2 unbranched dorsal and anal fin rays; 6-7 broad, wider than interspace, black bars on the body; 2 rows of black spots horizontally across the dorsal fin; a deeply emarginate caudal fin, with 2 vertical rows of black spots across the fin, and 9 + 8 branched caudal fin rays.

Erratum to: Molecular Characterization of a Lysophosphatidylcholine Acyltransferase Gene Belonging to the MBOAT Family in Ricinus communis L.

In the original publication of the article, figure 7 results were incorrectly published. Because of the discrepancies between our results published in Lipids 48(7):663–674, and others in the field with regards to Membrane Bound O-Acyltranferase (MBOAT) activity with 18:2n-6 and 18:3n-3 as substrates, we measured the activity of the castor lysophosphatidylcholine acyltransferase (RcLPCAT) using freshly prepared substrates. The 18:3-CoA and 18:2-CoA were prepared by chemical synthesis [1] and kindly provided by Dr. Stymne (Swedish University of Agricultural Sciences, Alnarp, Sweden). As indicated by our results using the new substrates, LPCAT activity was similar for 18:2 and 18:3 thioesters as it was for 18:1 and 16:1 thioesters, in agreement with the specificity recorded for Brassica LPCAT. These new results do not alter the major conclusion stated in our paper that MBOAT has limited activity with ricinoleoyl-CoA as a substrate, but does indicate it has similar activity with 18:2-CoA and 18:3-CoA as it does with 18:1-CoA and 16:1-CoA. The correct version of figure 7 is given below: RcLPCAT specificity using diverse acyl-CoA donors. LPCAT activity was assayed using 50 μM lysoPtdCho as the acceptor and different acyl-CoA as substrates at two concentrations, 10 μM (grey bars) or 40 μM (black bars) as indicated. The assay was performed as described in “Materials and Methods” of the published paper, in the presence of 30 μg of membrane protein extract prepared from yeast ale1 cells expressing RcLPCAT. Background LPLAT activities were determined from cells transformed with the pYES2 empty vector and the appropriate background rates were subtracted from the measured rate. The specific activity is presented and is expressed as nmol of released CoA min−1 μg−1 of membrane protein

Hormone replacement therapy enhances IGF-1 signaling in skeletal muscle by diminishing miR-182 and miR-223 expressions: a study on postmenopausal monozygotic twin pairs.

MiRNAs are fine-tuning modifiers of skeletal muscle regulation, but knowledge of their hormonal control is lacking. We used a co-twin case–control study design, that is, monozygotic postmenopausal twin pairs discordant for estrogen-based hormone replacement therapy (HRT) to explore estrogen-dependent skeletal muscle regulation via miRNAs. MiRNA profiles were determined from vastus lateralis muscle of nine healthy 54–62-years-old monozygotic female twin pairs discordant for HRT (median 7 years). MCF-7 cells, human myoblast cultures and mouse muscle experiments were used to confirm estrogen’s causal role on the expression of specific miRNAs, their target mRNAs and proteins and finally the activation of related signaling pathway. Of the 230 miRNAs expressed at detectable levels in muscle samples, qPCR confirmed significantly lower miR-182, miR-223 and miR-142-3p expressions in HRT using than in their nonusing co-twins. Insulin/IGF-1 signaling emerged one common pathway targeted by these miRNAs. IGF-1R and FOXO3A mRNA and protein were more abundantly expressed in muscle samples of HRT users than nonusers. In vitro assays confirmed effective targeting of miR-182 and miR-223 on IGF-1R and FOXO3A mRNA as well as a dose-dependent miR-182 and miR-223 down-regulations concomitantly with up-regulation of FOXO3A and IGF-1R expression. Novel finding is the postmenopausal HRT-reduced miRs-182, miR-223 and miR-142-3p expression in female skeletal muscle. The observed miRNA-mediated enhancement of the target genes’ IGF-1R and FOXO3A expression as well as the activation of insulin/IGF-1 pathway signaling via phosphorylation of AKT and mTOR is an important mechanism for positive estrogen impact on skeletal muscle of postmenopausal women.

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Fundamental Insights into the Electrochemical Performance of Chromium Doped LiCoPO4

High voltage cathode materials are promising technologies for increasing the energy density and thus increasing the range of electric vehicles. LiCoPO4 is known as a possible high voltage material, which is electrochemically active at 4.8 V vs. Li/Li+ with a theoretical capacity of 167 mAh/g [1], corresponding to a theoretical energy density of ~800 Wh/kg. Unfortunately, this material suffers of bad rate capability because of its very low ionic and electronic conductivity.To increase the ionic diffusion of the material, dopings of LiCoPO4 with 3%at Cr on the Li site and on the Co site are proposed. The syntheses are done by solid state method but different processes are used to dope on the Li site, nominally Li0.97Cr0.03CoPO4 (Yang et al [2] synthesis method) or on the Co site, nominally LiCo0.97Cr0.03PO4 (Wolfenstine et al [3]synthesis method). At the end of the synthesis, a ball milling step is added to reduce the particle size in order to improve the rate capability. Two different milling conditions are set: “soft” (400 rpm) and “hard” (1100 rpm). The first one seems to not damage the structure of the materials whereas the other one destroys the crystallinity and some impurities are identified by XRD. An additional annealing of the material ball milled under “hard” condition allows re-forming the phospho-olivine structure with good crystallinity. The synthetized materials are characterized by XRD, ICP and XAS (Cr K-edge and Co K- edge). Based on XAS analysis, no difference is noted in the Cr environment for the two syntheses and based on XRD, no side phase is detectable for all the samples. The Cr content of 3% is confirmed by ICP.The discharge capacities of the various samples are presented Figure 1. It can be seen that for a sample ball milled at 400 rpm, the Cr doped sample (LiCo0.97Cr0.03PO4; green bar in Fig. 1) is showing the best rate capability, whereas for a sample ball milled at 1100 rpm, it is the undoped LiCoPO4 (black bar in Fig. 1). The higher capacity and rate capability of the latter compared to the undoped LiCoPO4 ball milled at 400 rpm (red bar in Fig. 1) is due to its much smaller particle size and its higher specific surface area (»25 vs. »1 m2/g). Additionally, an unexpected huge difference is observed for the two chromium doped materials: LiCo0.97Cr0.03PO4 (green bar in Fig. 1) has much higher capacity and rate capability than Li0.97Cr0.03CoPO4 (orange bar in Fig. 1), even though XAS analysis suggests that the chromium dopant site is identical in both samples despite their different nominal dopant sites. Considering the recent work by Lee et al.4 on LiMO2 active materials, an excess of lithium in the material LiCo0.97Cr0.03PO4 compared to Li0.97Cr0.03CoPO4could be responsible for the better capacities.Acknowledgements: This work is financially supported by BMW.

Arterial stiffness and hypertension: chicken or egg?

Hypertension is highly prevalent in the United States and worldwide. In the United States, 1 in 3 adults (≈73 million people) have hypertension. The financial and human costs of hypertension are substantial. The estimated costs attributable to hypertension in the United States alone in 2010 were $70 billion direct costs for medical treatments and $24 billion indirect costs because of lost productivity.1 Awareness and treatment of hypertension have improved considerably during the past several decades: >80% of all people with hypertension are aware of the condition and 75% are using antihypertensive medications.2,3 However, despite enormous effort and treatment-related expenditures, only 53% of those with documented hypertension have their blood pressure controlled.3 Older age (Figure 1), left ventricular hypertrophy, and obesity are important risk factors for uncontrolled or drug-resistant hypertension.4 Importantly, the foregoing are also risk factors for increased aortic stiffness.5 Figure 1. Hypertension prevalence and control rates as a function of age in the National Health and Nutrition Examination Survey 2003 to 2004. Data derived from Wong et al.44 During the past 2 decades, measures of aortic stiffness have emerged as important risk factors for progression of blood pressure and incident cardiovascular disease. Carotid femoral pulse wave velocity (CFPWV), a measure of aortic wall stiffness, increases markedly with age, particularly after midlife. For example, Framingham Heart Study investigators have shown that the prevalence of CFPWV ≥12 m/s increases from a few percentage before 50 years of age to ≥60% after 70 years of age (Figure 2A). Importantly, elevated CFPWV is associated with high risk for incident hypertension (Figure 2B) and cardiovascular disease (Figure 2C). Figure 2C should be interpreted within the context that a normal value (<95th percentile) for CFPWV in a healthy Framingham Heart Study reference sample <50 years of age was 8.1 …

Neuromagnetic brain responses to other person's eye blinks seen on video.

Eye blinks, typically occurring 15–20 times per minute, rarely capture attention during face-to-face interaction. To determine the extent to which eye blinks affect the viewer's brain activity, we recorded magnetoencephalographic brain responses to natural blinks, and to the same blinks slowed down to 38% of the original speed. The stimuli were presented on video once every 2.3–6.2 s. As a control, we presented two horizontal black bars moving with the same time courses and the same extent as the eyelids in the blink video. Both types of blinks and bars elicited clear responses peaking at about 200 ms in the occipital areas, with no systematic differences between hemispheres. For the bars, these main responses were (as expected) weaker (by 24%) and later (by 33 ms) to slow-motion than normal-speed stimuli. For blinks, however, the responses to both normal-speed and slow-motion stimuli were of the same amplitude and latency. Our results demonstrate that the brain not only responds to other persons' eye blinks, but that the responses are as fast and of equal size even when the blinks are considerably slowed down. We interpret this finding to reflect the increased social salience of the slowed-down blinks that counteracted the general tendency of the brain to react more weakly and more slowly to slowly- vs. quickly-changing stimuli. This finding may relate to the social importance of facial gestures, including eye blinks.

Schistura phamhringi, a new stone loach from Chindwin Basin in Manipur,India (Cypriniformes: Nemacheilidae).

Schistura phamhringi, new stone loach, is described from Dutah Stream, tributary of the Yu River (Chindwin basin), near Larong Village, Chandel District, Manipur, India. It is distinguished from all its congeners by a unique combination of characters: 6-7 black saddles, each continued on both flanks forming broad diamond-shaped black bars with narrow ventral margin; bars superimposed on a grey stripe along lateral line; upper lip with numerous melanophores; black basicaudal bar arc-shaped; complete lateral line; and prominent oar-like suborbital flap on male.

H63D Genotying for Hemochromatosis: Helper or Hindrance?

H63D Genotying for Hemochromatosis: Helper or Hindrance?

Designing Ago2-specific siRNA/shRNA to Avoid Competition with Endogenous miRNAs.

Relatively large amounts of transfected siRNA can compete for Ago proteins and thus compromise endogenous miRNA function, potentially leading to toxicities. Here, we show that shRNA can also perturb endogenous miRNA function similarly. More importantly, we also show that the problem can be solved by designing shRNAs in the context of pre-miR-451 structure with completely complementary stem, which significantly improves the Ago2 specificity. This shRNA was shown to be Ago2-specific, and maintain target-silencing ability while avoiding competition with endogenous miRNAs by not competing for Agos 1, 3, and 4. We conclude that modified pre-miR-451 structure provides a general platform to design shRNAs that significantly reduce perturbation of miRNA function.

Hypoxia-inducible Factor-1α (HIF-1α) Protein Diminishes Sodium Glucose Transport 1 (SGLT1) and SGLT2 Protein Expression in Renal Epithelial Tubular Cells (LLC-PK1) under Hypoxia

In this work, we demonstrated the regulation of glucose transporters by hypoxia inducible factor-1α (HIF-1α) activation in renal epithelial cells. LLC-PK1 monolayers were incubated for 1, 3, 6, or 12 h with 0% or 5% O2 or 300 μm cobalt (CoCl2). We evaluated the effects of hypoxia on the mRNA and protein expression of HIF-1α and of the glucose transporters SGLT1, SGLT2, and GLUT1. The data showed an increase in HIF-1α mRNA and protein expression under the three evaluated conditions (p < 0.05 versus t = 0). An increase in GLUT1 mRNA (12 h) and protein expression (at 3, 6, and 12 h) was observed (p < 0.05 versus t = 0). SGLT1 and SGLT2 mRNA and protein expression decreased under the three evaluated conditions (p < 0.05 versus t = 0). In conclusion, our results suggest a clear decrease in the expression of the glucose transporters SGLT1 and SGLT2 under hypoxic conditions which implies a possible correlation with increased expression of HIF-1α.

Gaze characteristics of freely walking blowflies Calliphora vicina in a goal-directed task.

In contrast to flying flies, walking flies experience relatively strong rotational gaze shifts, even during overall straight phases of locomotion. These gaze shifts are caused by the walking apparatus and modulated by the stride frequency. Accordingly, even during straight walking phases, the retinal image flow is composed of both translational and rotational optic flow, which might affect spatial vision, as well as fixation behavior. We addressed this issue for an orientation task where walking blowflies approached a black vertical bar. The visual stimulus was stationary, or either the bar or the background moved horizontally. The stride-coupled gaze shifts of flies walking toward the bar had similar amplitudes under all visual conditions tested. This finding indicates that these shifts are an inherent feature of walking, which are not even compensated during a visual goal fixation task. By contrast, approaching flies showed a frequent stop-and-go behavior that was affected by the stimulus conditions. As sustained image rotations may impair distance estimation during walking, we propose a hypothesis that explains how rotation-independent translatory image flow containing distance information can be determined. The algorithm proposed works without requiring differentiation at the behavioral level of the rotational and translational flow components. By contrast, disentangling both has been proposed to be necessary during flight. By comparing the retinal velocities of the edges of the goal, its rotational image motion component can be removed. Consequently, the expansion velocity of the goal and, thus, its proximity can be extracted, irrespective of distance-independent stride-coupled rotational image shifts.

Acrossocheilus multistriatus, a new species of barbine fish (Teleostei: Cyprinidae) from the Zhujiang River basin, South China

A new barbine cyprinid fish, Acrossocheilus multistriatus sp. nov., is described from the Zhujiang River (Pearl River) basin in South China. It is separated from all other barred congeners except A. monticola by its unique coloration pattern of 8-12 vs. 5-7 vertical dark bars on the dorsum and flank. Although 8 vertical black bars are also present in specimens of A. monticola, the new species is distinct from it by having a well-developed (vs. poor-developed) lower lip, with or without a median interruption (vs. with a median interruption which wider than 1/2 mouth width) on lower jaw, the lower jaw entirely covered (vs. uncoverd) by the lower lip, body depth 22.57%-25.22% SL (vs. 25.64%-32.26% SL). Additional characteristices as follows: last simple dorsal-fin ray soft without serration; dark stripes on membranes between dorsal-fin rays; dark stripes absent on membranes between anal fin rays; maxillary barbels longer than eye diameter, extending to posterior edge of eyes.

Simulated validation and quantitative analysis of the blur of an integral image related to the pickup sampling effects

In an integral imaging (II) system, the pickup sampling effects play an important role in affecting the blur of an integral image. In this paper, the blur property of an integral image due to the pickup sampling artifacts is first analyzed. Then, a figure of merit-the edge blur width (EBW) of a white and black bar object is proposed to characterize the blur of the reconstructed image, and its theoretical model is derived in detail based on a continuous/discrete (C/D) sampling mechanism by considering both the pickup sampling and the reconstruction process. Further, the quantitative relationships of the blur with the pickup sampling parameters (the pixel number of each elemental image, the number of elemental images) are calculated by the EBW model and measured by C/D sampling II simulation experiments, respectively. We find out that the theoretical results have a good agreement with the estimated ones, and the minimum values of the EBW occurred periodically when the pixel number of an elemental image is an integral multiple of the magnification ratio.

우리나라 전복 양식장의 패각 천공성 다모류 감염현황

패각 및 석회기질을 천공하는 것으로 잘 알려져 있는 Polydora 속(Polychaeta, Spionidae) 다모류는 종종 전복을 포함한, 상업적으로 중요한 패류에 침입하여 성장률 및 육중량 감소와 상품가치를 하락시키다. 2012년 우리나라 전복 가두리 양식장 10개소를 대상으로 패각 천공성 다모류의 감염현황을 조사한 결과, 활전복에서는 5~99%, 죽은 전복 패각에서는 5.3~70.3%의 감염률을 보였다. 이들 전복은 진주층으로 덮힌 blister 및 패각변형이 일어났으며 패각 표면에는 Polydora가 서식하는 도관(burrow)으로 연결된 2개의 구멍이 확인되었다. 여기에서 분리된 Polydora는 성체의 길이가 40mm 이상으로 검은 띠가 있는 두드러진 palps, 꼬리 말단부위의 원반형 pygidium 및 4개의 eyespots을 가지는 것이 특징적이었다. 본 연구는 우리나라 전복 가두리 양식장의 패각 천공성 다모류 감염현황에 대한 첫 보고이다. The genus Polydora(Polychaeta, Spionidae) includes many species well known for their activity as borers. They often become harmful invaders by reducing the growth rate and meat yield of, or inducing the mortality of commercially important mollusck, abalone, Haiotis discus hannai. In 2012, the frequency of the Polydora was observed with 5~99% in live abalone and 5.3~70.3% in dead abalone shells of abalone sea-caged aquaculture system, Korea. There are many nacreous blister in the ventral margin and inner of the infestated abalone by abalone in response to the Polydora. A worm bored two holes in the shell and come in and out for ingestion the organic matters. They are more than 40 mm in length and had outstanding palps with black bars, disc form pygidium and 4 eyespots. This is the first record for the statue of Polydora infestation of sea-caged cultured abalone, Haliotis discus hannai in Korea.

A new killifish of the genus Melanorivulus from the upper Paran&amp;aacute; river basin, Brazil (Cyprinodontiformes: Rivulidae)

Melanorivulus leali, new species, from the Grande river drainage, south-eastern Brazil, is described. It differs from all other congeners by possessing a unique colour pattern, comprising red dots on body side arranged in chevron shaped rows, a broad dark grey stripe along the whole flank, flank light blue in males, dorsal and ventral portions of the caudal fin light orangish red in males, conspicuous orangish red bars on the middle of the caudal fin in males, and dorsal portion of the caudal-fin base with a small vertically elongated black spot. The presence of a black bar on the anterior and another on the posterior portion of the iris almost in contact with the pupil and the shape of the chevron-like rows of red spots on the flank, in which the angle is placed on the midline of the flank indicate that M. leali is more closely related to congeners endemic to the Paraná-Paraguay river system than to congeners endemic to the Amazonas river basin. This first record of the genus Melanorivulus from the Grande river drainage suggests that it may have formerly occupied a larger region of this basin, presently under severe process of deforestation and aquatic habitat decline.

Prolyl‐isomerase Pin1 controls normal and cancer stem cells of the breast

Mammary epithelial stem cells are fundamental to maintain tissue integrity. Cancer stem cells (CSCs) are implicated in both treatment resistance and disease relapse, and the molecular bases of their malignant properties are still poorly understood. Here we show that both normal stem cells and CSCs of the breast are controlled by the prolyl-isomerase Pin1. Mechanistically, following interaction with Pin1, Notch1 and Notch4, key regulators of cell fate, escape from proteasomal degradation by their major ubiquitin-ligase Fbxw7α. Functionally, we show that Fbxw7α acts as an essential negative regulator of breast CSCs' expansion by restraining Notch activity, but the establishment of a Notch/Pin1 active circuitry opposes this effect, thus promoting breast CSCs self-renewal, tumor growth and metastasis in vivo. In human breast cancers, despite Fbxw7α expression, high levels of Pin1 sustain Notch signaling, which correlates with poor prognosis. Suppression of Pin1 holds promise in reverting aggressive phenotypes, through CSC exhaustion as well as recovered drug sensitivity carrying relevant implications for therapy of breast cancers.