Biomedical subjects

Lian Li

Publications and source records attributed to Lian Li.

At least 37 records · Page 2Linked to original sources

PubMed2005

Investigation of neural progenitor cell induced angiogenesis after embolic stroke in rat using MRI.

Using MRI, we investigated dynamic changes of brain angiogenesis after neural progenitor cell transplantation in the living adult rat subjected to embolic stroke. Neural progenitor cells isolated from the subventricular zone (SVZ) of the adult rat were labeled by superparamagnetic particles and intracisternally transplanted into the adult rat 48 h after stroke (n = 8). Before and after the transplantation, an array of MRI parameters were measured, including high resolution 3D MRI and quantitative T1, T1sat (T1 in the presence of an off-resonance irradiation of the macromolecules of brain), T2, the inverse of the apparent forward transfer rate for magnetization transfer (kinv), cerebral blood flow (CBF), cerebral blood volume (CBV), and blood-to-brain transfer constant (Ki) of Gd-DTPA. The von Willerbrand factor (vWF) immunoreactive images of coronal sections obtained at 6 weeks after cell transplantation were used to analyze vWF immunoreactive vessels. MRI measurements revealed that grafted neural progenitor cells selectively migrated towards the ischemic boundary regions. In the ischemic boundary regions, angiogenesis confirmed by an increase in vascular density and the appearance of large thin wall mother vessels was coincident with increases of CBF and CBV (CBF, P < 0.01; CBV, P < 0.01) at 6 weeks after treatment, and coincident with transient increases of K(i) with a peak at 2 to 3 weeks after cell therapy. Relative T1, T1sat, T2, and kinv decreased in the ischemic boundary regions with angiogenesis compared to that in the non-angiogenic ischemic region (T1, P < 0.01 at 6 weeks; T1sat, P < 0.05 at 2 to 6 weeks; T2, P < 0.05 at 3 to 6 weeks; kinvP < 0.05 at 6 weeks). Of these methods, Ki appear to be the most useful MR measurements which identify and predict the location and area of angiogenesis. CBF, CBV, T1sat, T1, T2, and kinv provide complementary information to characterize ischemic tissue with and without angiogenesis. Our data suggest that select MRI parameters can identify the cerebral tissue destined to undergo angiogenesis after treatment of embolic stroke with cell therapy.

Algorithms↗

PubMed2005

Early prediction of gross hemorrhagic transformation by noncontrast agent MRI cluster analysis after embolic stroke in rat.

BACKGROUND AND PURPOSE: Our goal was to develop magnetic resonance indices, without image contrast agent enhancement, that predict hemorrhagic transformation (HT) in a rat model of embolic stroke. METHODS: Male Wistar rats subjected to embolic stroke with (n=12) or without (n=10) the combination treatment with recombinant tissue plasminogen activator and an anti-platelet glycoprotein IIb/IIIa antibody 7E3 F(ab')2 initiated at 4 hours after onset of stroke were investigated using a 7-T MRI system. Radiofrequency saturation T1 (T1sat) maps with magnetization transfer, apparent diffusion coefficient of water (ADCw) maps in 3 directions, and T2 maps were measured at 2, 24, and 48 hours after embolization. MRI data were analyzed individually and using 2D cluster plots. Histological measurements were obtained at 48 hours. RESULTS: Gross hemorrhage was detected at 48 hours in 7 (4 control, 3 treated) of 22 animals. The 2D cluster plot using MRI T1sat and ADCw maps obtained at 2 hours after stroke predicted all gross HT. The location of gross hemorrhage predicted by the 2D cluster plot was within 0.75 mm of the identifying MRI cluster. CONCLUSIONS: The 2D MRI cluster plot analysis using T1sat and ADCw maps acquired at 2 hours after the onset of embolic stroke predicts gross HT.

Animals↗

PubMed2005

Oxidative modifications and aggregation of Cu,Zn-superoxide dismutase associated with Alzheimer and Parkinson diseases.

Although oxidative stress has been strongly implicated in the pathogenesis of Alzheimer disease (AD) and Parkinson disease (PD), the identities of specific protein targets of oxidative damage remain largely unknown. Here, we report that Cu,Zn-superoxide dismutase (SOD1), a key antioxidant enzyme whose mutations have been linked to autosomal dominant neurodegenerative disorder familial amyotrophic lateral sclerosis (ALS), is a major target of oxidative damage in AD and PD brains. By using a combination of two-dimensional gel electrophoresis, immunoblot analysis, and mass spectrometry, we have identified four human brain SOD1 isoforms with pI values of 6.3, 6.0, 5.7, and 5.0, respectively. Of these, the SOD1 pI 6.0 isoform is oxidatively modified by carbonylation, and the pI 5.0 isoform is selectively accumulated in AD and PD. Moreover, Cys-146, a cysteine residue of SOD1 that is mutated in familial ALS, is oxidized to cysteic acid in AD and PD brains. Quantitative Western blot analyses demonstrate that the total level of SOD1 isoforms is significantly increased in both AD and PD. Furthermore, immunohistochemical and double fluorescence labeling studies reveal that SOD1 forms proteinaceous aggregates that are associated with amyloid senile plaques and neurofibrillary tangles in AD brains. These findings implicate, for the first time, the involvement of oxidative damage to SOD1 in the pathogenesis of sporadic AD and PD. This work suggests that AD, PD, and ALS may share a common or overlapping pathogenic mechanism(s) that could potentially be targeted by similar therapeutic strategies.

Aged↗

PubMed2005

Map-ISODATA demarcates regional response to combination rt-PA and 7E3 F(ab')2 treatment of embolic stroke in the rat.

PURPOSE: To investigate the ability of map-ISODATA (Iterative Self-Organizing Data Analysis Technique) to classify the different categories of ischemic damage in the lesion and to evaluate a combined (thrombolysis plus antiplatelet) treatment efficacy in an embolic stroke of rat. MATERIALS AND METHODS: Rats subjected to embolic stroke with (N=12) and without (N=10) rt-PA and 7E3 F(ab')2 treatment (4 hours after embolization) were followed (at 2, 24, and 48 hours post-MCAO) with magnetic resonance imaging (MRI) using T1, T2, and apparent diffusion coefficient of water (ADCw). ISODATA was computed from T1, T2, and ADCw maps. The signatures characterized by the map-ISODATA were compared with histological quantitative evaluation and were employed to demarcate the specific regions in the lesion. RESULTS: The signature described by map-ISODATA is highly correlated with the degree of tissue damage in the lesion and can distinguish the severity of ischemic tissue injury. Based upon map-ISODATA, ischemic lesion area can be divided into three specific regions, each characterized by a distinct evolution of injury and treatment response. The combined treatment significantly reduces the lesion size between 24 and 48 hours and improves the outcome 48 hours post-MCAO compared with the control group. CONCLUSION: Map-ISODATA provides an accurate means to identify lesion area, to distinguish ischemic damage, and to detect treatment response. 7E3 F(ab')2 extends the rt-PA treatment window to at least four hours after the onset of embolic stroke of rat.

Analysis of Variance↗

PubMed2005

Analysis of combined treatment of embolic stroke in rat with r-tPA and a GPIIb/IIIa inhibitor.

Suppression of platelet activation improves the efficacy of thrombolytic therapy for stroke. Thus, combination treatment with recombinant tissue plasminogen activator (r-tPA) and 7E3 F(ab')2, a GPIIb/IIIa inhibitor that binds the platelet to fibrin, may improve the efficacy of thrombolytic therapy in embolic stroke. Magnetic resonance imaging (MRI) was used to monitor treatment response in rats subjected to embolic middle cerebral artery (MCA) occlusion (MCAo). Animals were randomized into treated (n=12) and control (n=10) groups and received intravenous combination therapy or saline, respectively, 4 hours after MCAo. Magnetic resonance imaging (MRI) measurements performed 1 hour after MCAo showed no difference between groups. However, an increased incidence (50%) of MCA recanalization was found in the treated group at 24 hours compared with 20% in the control group. The area of low cerebral blood flow at 24 and 48 hours was significantly smaller in the combination treatment group, and the lesion size, as indicated from the T2 and T1 maps, differed significantly between groups. Fluorescence microscopy measurements of cerebral microvessels perfused with fluorescein isothiocyanate-dextran and measurements of infarct volume revealed that the combination treatment significantly increased microvascular patency and reduced infarct volume, respectively, compared with the control rats. The efficacy of combination treatment 4 hours after ischemia is reflected by MRI indices of tissue perfusion, MCA recanalization, and reduction of lesion volume. The treatment also reduced secondary microvascular perfusion deficits.

Animals↗

PubMed2005

Quantitative evaluation of BBB permeability after embolic stroke in rat using MRI.

We sought to identify magnetic resonance imaging (MRI) parameters that can identify as well as predict disruption of the blood-brain barrier (BBB) after embolic stroke in the rat. Rats subjected to embolic stroke with (n=13) and without (n=13) rt-PA treatment were followed with MRI using quantitative permeability-related parameters, consisting of: transfer constant (K(i)) of Gd- DTPA, the distribution volume (V(p)) of the mobile protons, and the inverse of the apparent forward transfer rate for magnetization transfer (k(inv)), as well as the apparent diffusion coefficient of water (ADC(w)), T2, and cerebral cerebral blood flow (CBF). Tissue progressing to fibrin leakage resulting from BBB disruption and adjacent tissue were then analyzed to identify MRI markers that characterize BBB disruption. Animals were killed after final MRI measurements at 24 h after induction of embolic stroke and cerebral tissues were perfused and stained to detect fibrin leakage. K(i), V(p), and k(inv) were the most sensitive early (2 to 3 h) indices of the cerebral tissue that progresses to fibrin leakage. Cerebral blood flow was not significantly different between ischemic tissue with a compromised and an intact BBB. Our data indicate that compromise of the BBB can be sensitively predicted using a select set of MR parameters.

Animals↗

PubMed2005

[Inhibitory effects of Galectin-3 on the inflammatory cytokines and chemokines in guinea pig asthma models].

OBJECTIVE: To elucidate the roles of interleukin-5 (IL-5), Eotaxin, and CCR-3 in eosinophilic inflammation in guinea pig asthma models and investigate the inhibitory effects of Galectin-3. METHODS: Thirty-two guinea pigs were randomly assigned to control group, asthma group, Galectin-3 intervention group, and dexamethasone (DXM) intervention group. Asthma models were established by sensitizing-challenging the animals with ovalbumin(OVA). The asthmatic animals were treated with Galectin-3 at 0.5 mg/kg, or DXM at 1 mg/kg, respectively,by peritoneally injection one hour before each aerosol challenge from the 14th day to 16th day after sensitization while the control animals were treated with normal saline. The specimens of peripheral blood, bone marrow, and lung tissue on slides were prepared respectively and stained with HE. Then the total number and percentage of eosinophils (EOS) were counted. The lung tissue slide was stained immunochemically with anti-IL-5 polyclonal antibody, anti-Eotaxin polyclonal antibody, and anti-CCR-3 polyclonal antibody, respectively. The immunoactive cells were counted and represented as percentages in total cells. RESULTS: The amounts of EOS in peripheral blood, bone marrow,and lung tissue as well as percentages of IL-5, Eotaxin,and CCR-3 immunoactive cells in the lung tissue from asthma group were increased significantly, compared to those from control group. DXM significantly decreased the amounts of EOS, percentages of IL-5, Eotaxin, and CCR-3 immunoactive cells (P < 0.05). Galectin-3 had an equivalent suppressive effects on the amounts of EOS and IL-5+ cells with DXM (P > 0.05) and down-regulated CCR-3 expression (P < 0.05) to a less extent when compared to DXM (P < 0.05), but had minimal effect on Eotaxin expression (P > 0.05). CONCLUSION: This study provides further evidence for an eosinophil recruitment from bone marrow to circulation blood to lung in asthmatic response, in which overexpression of IL-5, Eotaxin, and CCR-3 could be involved. Galectin-3, a selective inhibitor of IL-5 mRNA transcription, might potentially suppress eosinophilc inflammation and be a compromising specific anti-asthma reagent.

Animals↗

PubMed2005

[Building immune microsphere against tumor necrosis factor-alpha (TNF-alpha)].

We have constructed the immune microsphere against tumor necrosis factor-alpha (TNF-alpha) prospectively, hoping to establish the experiment groundwork in more researches which could be used in specific elimination of the TNF-alpha by blood purification method for the future. The recombinant human tumor necrosis factor-alpha monoclonal antibody (rHTNF-alpha McAb) was wrapped on the polystyrene microsphere (PSM) carrier connecting poly-L-lysine (PLL) beforehand. They were earmarked by the fluorescein isothiocyanate (FITC) respectively. The packing conditions were examined using the inversted and fluorescence microscopes and the spectrophotometer. The results showed that the best conditions for wrapping were 20 degrees C, pH9.5 and 60 minutes. The PLL content was not changed in the washing fluid after coating, which indicated the wrapping was quite firm. At the same temperature and same coating time, the rHTNF-alpha McAb coated on the PLL was obviously substantial when the concentration of glutaraldehyde solution was 0.2%. The findings demonstrated that the built immune microsphers can be used as a novel adsorption material. This method is simple and economic, and it offers a new approach to the related studies.

Antibodies, Monoclonal↗

PubMed2004

MRI evaluation of treatment of embolic stroke in rat with intra-arterial and intravenous rt-PA.

Using magnetic resonance imaging (MRI), we investigated treatment of a rat model of embolic stroke with rt-PA via intra-arterial (IA) and intravenous (IV) routes of administration. Rats were treated with rt-PA by either IA (n = 13) or IV (n = 13) routes at 3 h after stroke induction. Diffusion, perfusion, T2, and magnetization transfer MRI were performed prior to and at 1-3 and at 24 h after embolization. The IA treated group exhibited smaller lesion volumes than the IV treated group (p = 0.02). The relative areas with low ADCW and cerebral blood flow (CBF) after IA rt-PA intervention were significantly (p < or = 0.03) smaller than those in the IV treated group at 24 h after embolization. Significant differences (p < 0.02) between IA and IV treated groups in the relative area with high T2 and inverse of the apparent forward transfer rate of magnetization (kINV) in the ipsilateral hemisphere were also detected at 24 h after embolization. The IA treated group exhibited less intracerebral hemorrhage (27%) than the IV treated (64%) groups. Our data suggest that the beneficial effects of IA rt-PA treatment can be detected by changes in CBF, ADCW, T2, and kINV.

Animals↗

PubMed2004

Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal hydrolase L1 associated with idiopathic Parkinson's and Alzheimer's diseases.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative diseases that occur either in relatively rare, familial forms or in common, sporadic forms. The genetic defects underlying several monogenic familial forms of AD and PD have recently been identified, however, the causes of other AD and PD cases, particularly sporadic cases, remain unclear. To gain insights into the pathogenic mechanisms involved in AD and PD, we used a proteomic approach to identify proteins with altered expression levels and/or oxidative modifications in idiopathic AD and PD brains. Here, we report that the protein level of ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), a neuronal de-ubiquitinating enzyme whose mutation has been linked to an early-onset familial PD, is down-regulated in idiopathic PD as well as AD brains. By using a combination of two-dimensional gel electrophoresis and mass spectrometry, we have identified three human brain UCH-L1 isoforms, a full-length form and two amino-terminally truncated forms. Our proteomic analyses reveal that the full-length UCH-L1 is a major target of oxidative damage in AD and PD brains, which is extensively modified by carbonyl formation, methionine oxidation, and cysteine oxidation. Furthermore, immunohistochemical studies show that prominent UCH-L1 immunostaining is associated with neurofibrillary tangles and that the level of soluble UCH-L1 protein is inversely proportional to the number of tangles in AD brains. Together, these results provide evidence supporting a direct link between oxidative damage to the neuronal ubiquitination/de-ubiquitination machinery and the pathogenesis of sporadic AD and PD.

Alzheimer Disease↗

PubMed2004

[Signal transduction pathways and transcription factors involved in luteinizing hormone beta subunit gene expression].

The pulsatile pattern of the hypothalamic hormone gonadotropin-releasing hormone (GnRH) plays a critical role in reproductive function by regulating the biosynthesis and secretion of the pituitary gonadotropins. Follicle-stimulating hormone (FSH) and Luteinizing hormone (LH) are heterodimeric glycoproteins composed of a common peptide, the glycoprotein hormone subuint alpha, and either a specific FSHbeta or LHbeta polypeptide. GnRH regulates LHbeta gene expression through GnRH receptor activation of the protein kinase C (PKC) and calcium signaling cascades. Recently, many transcription factors, such as early growth response-1 (Egr-1), steroidogenic factor-1 (SF-1), Ptx1 and Sp1, have been recognized to be involved in expression of the LHbeta gene through binding to the promoter region of LHbeta gene.

Animals↗

PubMed2004

Effect of vasoactive intestinal peptide on pulmonary surfactants phospholipid synthesis in lung explants.

AIM: To investigate the effect of vasoactive intestinal peptide (VIP) on pulmonary surfactants (PS) phospholipid synthesis in cultured lung explants. METHODS: Lung explants were cultured with serum-free medium, [methyl-3H]choline incorporation, total phospholipid, phosphatidylcholine, activity of choline-phosphate cytidylyltransferase (CCT) and CCTalpha mRNA level in lung explants were determined. RESULTS: (1) VIP (10(-10)-10(-7) mol/L) for 16 h promoted [methyl-3H]choline incorporation in dose dependence and VIP (10(-8) mol/L) for 2 h-16 h promoted [methyl-3H]choline incorporation in time dependence. (2) VIP (10(-8) mol/L) enhanced the contents of total phospholipids and phosphatidylcholine in lung explants. (3) VIP (10(-10)-10(-7) mol/L) elevated microsomal CCT activity of lung explants in dose dependence. (4) VIP (10(-8) mol/L) increased expression of CCTalpha mRNA in lung explants and alveolar type II cells (ATII). (5) [D-P-Cl-Phe(6)-Leu(17)]-VIP (10(-6) mol/L), a VIP receptors antagonist, abolished the increase of [3H]choline incorporation, microsomal CCT activity and CCTalpha mRNA level induced by VIP (10(-8) mol/L) in lung explants. CONCLUSION: VIP could enhance synthesis of phosphatidylcholine, the major component of pulmonary surfactants by enhancing microsomal CCT activity and CCTalpha mRNA level via VIP receptor-mediated pathway.

Animals↗

PubMed2004

[A new impulse noise filter based on pulse coupled neural network].

This paper presents a new impulse noise filter based on pulse coupled neural networks according to the apparent difference of gray value between noised pixels and the pixels around them. Comparing with the state-of-the-art denoised PCNN filter, the step by step modifying algorithm based on PCNN also, the new PCNN filter suggested in this paper costs less computation and less execution time. At the same time this new PCNN filter has been compared with other nonlinear filters, such as median filter, the stack filter based on omnidirectional structural elements constrains, the Omnidirectional morphology Open-Closing maximum filter (OOCmax) and the Omnidirectional morphology Close-Opening minimum (OCOmin) filter. The results of simulation shows that this algorithm is superior to standard median filter, the state-of-the-art PCNN filter, the maximal, minimal morphological filter with omnidirectional structuring elements, and the optimal stack filter based on omnidirectional structural elements constrains in the aspect of the impulse noise removal. What is more important is that this algorithm can keep the details of images more effectively.

Computer Simulation↗

PubMed2003

Familial Parkinson's disease-associated L166P mutation disrupts DJ-1 protein folding and function.

Mutations in DJ-1, a protein of unknown function, were recently identified as the cause for an autosomal recessive, early onset form of familial Parkinson's disease. Here we report that DJ-1 is a dimeric protein that exhibits protease activity but no chaperone activity. The protease activity was abolished by mutation of Cys-106 to Ala, suggesting that DJ-1 functions as a cysteine protease. Our studies revealed that the Parkinson's disease-linked L166P mutation impaired the intrinsic folding propensity of DJ-1 protein, resulting in a spontaneously unfolded structure that was incapable of forming a homodimer with itself or a heterodimer with wild-type DJ-1. Correlating with the disruption of DJ-1 structure, the L166P mutation abolished the catalytic function of DJ-1. Furthermore, as a result of protein misfolding, the L166P mutant DJ-1 was selectively polyubiquitinated and rapidly degraded by the proteasome. Together these findings provide insights into the molecular mechanism by which loss-of-function mutations in DJ-1 lead to Parkinson's disease.

Amino Acid Sequence↗

PubMed2003

Crystal structure of DJ-1/RS and implication on familial Parkinson's disease.

DJ-1 is a protein involved in multiple physiological processes, including cancer, Parkinson's disease, and male fertility. It is unknown how DJ-1 functions in the apparently different systems. The crystal structure of DJ-1 at 1.6 A resolution shows that DJ-1 is a helix-strand-helix sandwich and forms a dimer. The DJ-1 structure is similar to the members of the intracellular protease PfpI family. However, the catalytic triad of Cys-His-Glu is not strictly conserved in DJ-1, implying that DJ-1 has a different catalytic mechanism if it acts as a protease or DJ-1 serves as a regulatory protein in the physiological processes. The structure shows that Leu166 positions in the middle of a helix and thus predicts that the L166P mutation will bend the helix and impact the dimerization of DJ-1. As a result, the conformational changes may diminish the DJ-1 binding with its partner, leading to the familial Parkinson's disease caused by the single L166P mutation.

Catalytic Domain↗

PubMed2003

Patlak plots of Gd-DTPA MRI data yield blood-brain transfer constants concordant with those of 14C-sucrose in areas of blood-brain opening.

The blood-to-brain transfer rate constant (K(i)) of Gd-DTPA was determined in MRI studies of a rat model of transient cerebral ischemia. The longitudinal relaxation rate, R(1), was estimated using repeated Look-Locker measurements. A model-independent analysis of deltaR(1), the Patlak plot, produced maps of K(i) for Gd-DTPA and the distribution volume of the mobile protons (V(p)) with intravascular-Gd changed R(1)'s. The K(i)'s of Gd-DTPA were estimated in regions of interest with blood-brain barrier (BBB) opening (regions of interest, ROIs) and compared to those of (14)C-sucrose determined shortly thereafter by quantitative autoradiography. The K(i)'s for both Gd-DTPA and sucrose were much higher than normal within the ROIs (n = 7); linear regression of K(i) for Gd-DTPA vs. K(i) for sucrose yielded a slope of 0.43 +/- 0.11 and r(2) = 0.72 (P = 0.01). Thus, K(i) for Gd-DTPA varied in parallel with, but was less than, K(i) for sucrose. In the ROIs, mean V(p) was 0.071 ml g(-1) and much higher than mean vascular volume estimated by dynamic-contrast-enhancement (0.013 ml g(-1)) or mean V(p) in contralateral brain (0.015 ml g(-1)). This elevated V(p) may reflect increased capillary permeability to water. In conclusion, K(i) can be reliably calculated from Gd-DTPA-MRI data by Patlak plots.

Animals↗

PubMed2002

Staring, a novel E3 ubiquitin-protein ligase that targets syntaxin 1 for degradation.

Syntaxin 1 is an essential component of the neurotransmitter release machinery, and regulation of syntaxin 1 expression levels is thought to contribute to the mechanism underlying learning and memory. However, the molecular events that control the degradation of syntaxin 1 remain undefined. Here we report the identification and characterization of a novel RING finger protein, Staring, that interacts with syntaxin 1. Staring is expressed throughout the brain, where it exists in both cytosolic and membrane-associated pools. Staring binds and recruits the brain-enriched E2 ubiquitin-conjugating enzyme UbcH8 to syntaxin 1 and facilitates the ubiquitination and proteasome-dependent degradation of syntaxin 1. These findings suggest that Staring is a novel E3 ubiquitin-protein ligase that targets syntaxin 1 for degradation by the ubiquitin-proteasome pathway.

Amino Acid Sequence↗

PubMed2002

Huntingtin-associated protein 1 interacts with hepatocyte growth factor-regulated tyrosine kinase substrate and functions in endosomal trafficking.

Huntingtin-associated protein 1 (HAP1) is a novel protein of unknown function with a higher binding affinity for the mutant form of Huntington's disease protein huntingtin. Here we report that HAP1 interacts with hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs), a mammalian homologue of yeast vacuolar protein sorting protein Vps27p involved in the endosome-to-lysosome trafficking. This novel interaction was identified in a yeast two-hybrid screen using full-length Hrs as bait, and confirmed by in vitro binding assays and co-immunoprecipitation experiments. Deletion analysis reveals that the association of HAP1 with Hrs is mediated via a coiled-coil interaction between the central coiled-coil domains of both proteins. Immunofluorescence and subcellular fractionation studies show that HAP1 co-localizes with Hrs on early endosomes. Like Hrs, overexpression of HAP1 causes the formation of enlarged early endosomes, and inhibits the degradation of internalized epidermal growth factor receptors. Whereas overexpression of HAP1 does not affect either constitutive or ligand-induced receptor-mediated endocytosis, it potently blocks the trafficking of endocytosed epidermal growth factor receptors from early endosomes to late endosomes. These findings implicate, for the first time, the involvement of HAP1 in the regulation of vesicular trafficking from early endosomes to the late endocytic compartments.

Animals↗