Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P67775 (alpha isoform)
797 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Paxillin, a focal adhesion protein, exists as multiple isoforms in humans (alpha, beta, and gamma). To understand more about the physiological role of each isoform, we have employed the mouse system. We found that although the alpha and beta isoforms are present in the mouse, the gamma isoform is not. The alpha isoform protein was detected clearly in most adult tissues, whereas the beta isoform protein was almost undetectable except in spleen, testis, thymus, and lung. On the other hand, mRNAs of both isoforms were detectable in all tissues we examined. High levels of the beta isoform protein was detected in peritoneal exudate macrophage cells in adult mouse as well as in cultured fibroblasts, together with the alpha isoform. The alpha isoform was expressed at a constant level throughout the embryonic stages we examined, whereas the beta isoform protein was detected at the mid-stages of development and increased to levels almost equal to those of the alpha isoform during the late stages of embryogenesis. Therefore, unlike the alpha isoform, expression of the beta isoform protein is restricted in adult tissues. Moreover, we showed that alpha and beta isoforms were colocalized within the same focal adhesion plaques, and cytoplasmic pools of both isoforms exist in the perinuclear area, colocalized with the Golgi apparatus.
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PMID:Paxillin isoforms in mouse. Lack of the gamma isoform and developmentally specific beta isoform expression. 971 67

Several alterations in fibroblasts of Alzheimer's disease (AD) patients have been described, including alterations in calcium regulation, protein kinase C (PKC), and potassium (K+) channels. Studies have also found reduced levels of the alpha isoform of PKC in brains and fibroblasts of AD patients. Since PKC is known to regulate ion channels, we studied K+ channel activity in fibroblasts from AD patients in the presence of (2S, 5S)-8-(1-decynyl)benzolactam (BL), a novel activator of PKC with improved selectivity for the alpha, beta, and gamma isoforms. We present evidence for restoration of normal K+ channel function, as measured by TEA-induced [Ca2+]i elevations, due to activation of PKC by BL. Representative patch-clamp data further substantiate the effect of BL on restoration of 113pS K+ channel activity. Immunoblotting analyses using an alpha-isozyme-specific PKC antibody confirm that BL-treated fibroblasts of AD patients show increased PKC activation. The present study suggests that PKC activator-based restoration of K+ channels may offer another approach to the investigation of AD pathophysiology, which in turn could lead to the development of a useful model for AD therapeutics.
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PMID:Restoration of TEA-induced calcium responses in fibroblasts from Alzheimer's disease patients by a PKC activator. 984 89

Activation of protein kinase C is known to favor the alpha-secretase processing of the Alzheimer's disease (AD) amyloid precursor protein (APP), resulting in the generation of non-amyloidogenic soluble APP (sAPP). Consequently, the relative secretion of amyloidogenic Abeta1-40 and Abeta1-42(3) is reduced. This is particularly relevant since fibroblasts and other cells expressing APP and presenilin AD mutations secrete increased amounts of total Abeta and/or increased ratios of Abeta1-42(3)/Abeta1-40. Interestingly, PKC defects have been found in AD brain alpha and beta isoforms) and in fibroblasts (alpha isoform) from AD patients. Here, we use a novel PKC activator (benzolactam, BL) with improved selectivity for the alpha, beta and gamma isoforms to enhance sAPP secretion in fibroblasts from AD patients and in PC12 cells. Incubation (2 h) of AD fibroblasts with BL (1 and 10 microM) resulted in significant increases of sAPP secretion over basal levels. sAPP secretion in BL-treated AD cells was also slightly higher compared to control BL-treated fibroblasts, which only showed significant increases of sAPP secretion after treatment with 10 microM BL. Staurosporine (a PKC inhibitor) eliminated the effects of BL in both control and AD fibroblasts. BL and a related compound (LQ12) also caused an approximately 3-fold sAPP secretion in PC12 cells. The use of a novel and possibly non-tumorigenic PKC activator may prove useful to favor non-amyloidogenic APP processing and is, therefore, of potential therapeutic value.
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PMID:Benzolactam (BL) enhances sAPP secretion in fibroblasts and in PC12 cells. 1032 81

Retinoid X receptor (RXR) is a nuclear receptor that functions as an obligate heterodimeric partner of peroxisome proliferator-activator receptor (PPAR). Studies have shown that the alpha isoform of RXR and PPARgamma act synergistically to regulate gene expression and insulin action. The aim of the current study was to compare the expression and regulation of RXR in the primary insulin-sensitive tissue, skeletal muscle, of various degrees of insulin-resistant states including obese type 2 diabetic (T2D), obese nondiabetic (OND), and lean nondiabetic (LND) subjects. Insulin action/resistance was determined by a 3-hour hyperinsulinemic, euglycemic (5.0 to 5.5 mmol/L) clamp. Percutaneous biopsy of the vastus lateralis muscle was performed before and after the clamp. RXRalpha mRNA was measured using a quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assay, while protein was determined by Western blotting. All 3 isoforms of RXR, alpha, beta, and gamma, were present in skeletal muscle. Protein expression of RXR isoforms did not differ between groups; RXR alpha mRNA was also similar between groups. Neither RXR alpha mRNA, RXR -beta nor -gamma protein displayed significant relationships with any of the clinical or laboratory parameters measured, including insulin sensitivity. RXR alpha exhibited a negative correlation with free fatty acids levels (r, -.42, P <.05). There was also no relationship between RXR alpha and PPARgamma protein levels. RXR alpha mRNA was unaltered following insulin infusion. We conclude that RXR isoform (alpha, beta, gamma) expression is not tightly controlled by insulin, insulin resistance or type 2 diabetes. Instead, RXR isoforms are likely constitutive proteins or controlled by other factors.
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PMID:Retinoid X receptor expression in skeletal muscle of nondiabetic, obese and type 2 diabetic individuals. 1143 90

The exocytosis of insulin from pancreatic beta-cells is closely related to intracellular elevation of Ca(2+). The effects of Ca(2+) may be mediated by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). Four subunits of CaMKII, termed alpha, beta, gamma, and delta, are encoded by distinct genes, and various isoforms of these subunits exist as different splicing variants. In the brain, phosphorylation of synapsin I by the alpha isoform induces neurotransmitter release. In order to clarify whether phosphorylation of synapsin I by CaMKII was involved in insulin exocytosis, we cloned the isoforms of CaMKII and synapsin I from mouse insulinoma MIN6 cells. We found that beta'e and delta2 are the major isoforms of CaMKII and that synapsin Ib is a major isoform of synapsin I in MIN6 cells. It was interesting that delta2 and synapsin Ib were co-localized with insulin secretory granules in the cells. Treatment of MIN6 cells with glucose and tolbutamide rapidly activated CaMKII. Immunoblot analysis with two antibodies against synapsin I phosphorylated by CaMKII demonstrated the increase in phosphorylation of synapsin I by the secretagogues. Furthermore, the secretagogue-induced phosphorylation of synapsin I and insulin secretion were potentiated by transient overexpression of the beta'e or delta2 isoform. These results suggest that activation of CaMKII and the concomitant phosphorylation of synapsin I induce insulin exocytosis from pancreatic beta-cells.
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PMID:New aspects of neurotransmitter release and exocytosis: involvement of Ca2+/calmodulin-dependent phosphorylation of synapsin I in insulin exocytosis. 1450 Nov 48

The p63 gene generates transactivating and N-terminally truncated transcripts (DeltaNp63) initiated by different promoters. Alternative splicing gives rise to three different C termini, designated alpha, beta, and gamma. In the ocular epithelium, the corneal stem cells, which are segregated in the basal layer of the limbus, contain the alpha isoform but not beta or gamma. Holoclones derived from the limbus are rich in alpha, meroclones contain little, and paraclones contain none. In normal resting corneal epithelium, p63 of all isoforms is absent. Upon corneal wounding, cells originating from the limbus and containing alpha migrate progressively through the epithelium of the peripheral and central cornea. In the absence of an attached limbus, no alpha isoform appears in the corneal epithelium. When migrating cells containing the alpha isoform appear in the wounded corneal epithelium, they are confined to the basal layer, but the suprabasal cells, not only of the cornea but of the limbus as well, contain mRNA encoding beta and gamma. These data support the concept that the alpha isoform of p63 is necessary for the maintenance of the proliferative potential of limbal stem cells and their ability to migrate over the cornea. The beta and gamma isoforms, being suprabasal and virtually absent from the resting limbus, are not stem cell markers but are likely to play a role in epithelial differentiation specifically during the process of corneal regeneration.
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PMID:Isoforms of DeltaNp63 and the migration of ocular limbal cells in human corneal regeneration. 1598 86

The aim of this study was to investigate the role of TAp63 and DeltaNp63 isoforms in uterine cervical cancers. The messenger RNA (mRNA) and protein expressions of TA and DeltaN forms as well as alpha, beta, and gamma isoforms of p63 were studied in seven SiHa, ME-180, SNU17, SNU902, SNU1160, SNU703, and SNU1299 human papillomavirus (HPV)-positive uterine cervical squamous cell carcinoma (SCC) cell lines, one HT3 HPV-negative SCC cell line, and one HeLa adenocarcinoma cell line using reverse transcription-polymerase chain reaction (RT-PCR) and western blotting. Fresh nonneoplastic and neoplastic tissues of uterine cervical and endometrial cancers were also studied. RT-PCR for TA and DeltaN form and three isoforms of p63 showed positive bands for both TA and DeltaN forms and for all three isoforms in cervical cancer cell lines but weak band for alpha isoform in HPV-negative HT3 SCC cell line and no band for beta isoform in HeLa adenocarcinoma cell line. RT-PCR for TA and DeltaN and three isoforms of p63 mRNA in tissue samples showed positive bands in almost all samples, except for gamma isoform, the expression was weak or absent in nonneoplastic tissues compared with neoplastic tissues. In western blotting, cancer cell lines and both nonneoplastic and neoplastic tissue samples showed expression of TA and DeltaN, and gamma isoform but beta isoform expression with or without alpha isoform was only found in cancer cell lines and neoplastic tissues. beta isoform, possibly of DeltaNp63, may be considered as an important isoform in uterine cervical squamous cell carcinogenesis.
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PMID:Reverse transcription-polymerase chain reaction and western blotting analysis for detection of p63 isoforms in uterine cervical cancers. 1688 78

The aim of the current study was to characterize the effects of chemical ischemia and reperfusion at the transductional level in the brain. Protein kinase C isoforms (alpha, beta(1), beta(2), gamma, delta and epsilon) total levels and their distribution in the particulate and cytosolic compartments were investigated in superfused rat cerebral cortex slices: (i) under control conditions; (ii) immediately after a 5-min treatment with 10mM NaN(3), combined with 2mM 2-deoxyglucose (chemical ischemia); (iii) 1h after chemical ischemia (reperfusion). In control samples, all the PKC isoforms were detected; immediately after chemical ischemia, PKC beta(1), delta and epsilon isoforms total levels (cytosol+particulate) were increased by 2.9, 2.7 and 9.9 times, respectively, while alpha isoform was slightly reduced and gamma isoform was no longer detectable. After reperfusion, the changes displayed by alpha, beta(1), gamma, delta and epsilon were maintained and even potentiated, moreover, an increase in beta(2) (by 41+/-12%) total levels became significant. Chemical ischemia-induced a significant translocation to the particulate compartment of PKC alpha isoform, which following reperfusion was found only in the cytosol. PKC beta(1) and delta isoforms particulate levels were significantly higher both in ischemic and in reperfused samples than in the controls. Conversely, following reperfusion, PKC beta(2) and epsilon isoforms displayed a reduction in their particulate to total level ratios. The intracellular calcium chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, 1mM, but not the N-methyl-d-asparate receptor antagonist, MK-801, 1muM, prevented the translocation of beta(1) isoform observed during ischemia. Both drugs were effective in counteracting reperfusion-induced changes in beta(2) and epsilon isoforms, suggesting the involvement of glutamate-induced calcium overload. These findings demonstrate that: (i) PKC isoforms participate differently in neurotoxicity/neuroprotection events; (ii) the changes observed following chemical ischemia are pharmacologically modulable; (iii) the protocol of in vitro chemical ischemia is suitable for drug screening.
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PMID:Differential activation of protein kinase C isoforms following chemical ischemia in rat cerebral cortex slices. 1696 62

Autotaxin is a type II ectonucleotide pyrophosphate phosphodiesterase enzyme. It has been recently discovered that it also has a lysophospholipase D activity. This enzyme probably provides most of the extracellular lysophosphatidic acid from lysophosphatidylcholine. The cloning and tissue distribution of the three isoforms (imaginatively called alpha, beta, and gamma) from human and mouse are reported in this study, as well as their tissue distribution by PCR in the human and mouse. The fate of the alpha isoform from human was also studied after purification and using mass spectrometry. Indeed, this particular isoform expresses the intron 12 in which a cleavage site is present, leading to a rapid catabolism of the isoform. For the human isoform gamma and the total autotaxin mRNA expression, quantitative PCR is presented in 21 tissues. The isoforms were expressed in two different hosts, insect cells and Chinese hamster ovary cells, and were highly purified. The characteristics of the six purified isoforms (pH and temperature dependence, K(m) and V(max) values, and their dependence on metal ions) are presented in this study. Their sensitivity to a small molecule inhibitor, hypericin, is also shown. Finally, the specificity of the isoforms toward a large family of lysophosphatidylcholines is reported. This study is the first complete description of the reported autotaxin isoforms.
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PMID:Murine and human autotaxin alpha, beta, and gamma isoforms: gene organization, tissue distribution, and biochemical characterization. 1817 5

Notch signaling is associated with prostate osteoblastic bone metastases and calcium/calmodulin-dependent kinase II (CaMKII) is associated with osteoblastogenesis of human mesenchymal stem cells. Here we show that prostate cancer cell lines C4-2B and PC3, both derived from bone metastases and express Notch-1, have all four isoforms of CaMKII (alpha, beta, gamma, delta). In contrast, prostate cancer cell lines LNcaP and DU145, which are not derived from bone metastases and lack the Notch-1 receptor, both lack the alpha isoform of CaMKII. In addition, DU145 cells also lack the beta-isoform. In C4-2B cells, inhibition of CaMKII by KN93 or gamma-secretase by L-685,458 inhibited the formation of the cleaved form of Notch-1 thus inhibiting Notch signaling. KN93 inhibited down stream Notch-1 signaling including Hes-1 gene expression, Hes-1 promoter activity, and c-Myc expression. In addition, both KN93 and L-685,458 inhibited proliferation and Matrigel invasion by C4-2B cells. The activity of gamma-secretase was unaffected by KN93 but markedly inhibited by L-685,458. Inhibition of the expression of alpha, beta, or gamma-isoform by siRNA did not affect Hes-1 gene expression, however when expression of one isoform was inhibited by siRNA, there were compensatory changes in the expression of the other isoforms. Over-expression of CaMKII-alpha increased Hes-1 expression, consistent with Notch-1 signaling being at least partially dependent upon CaMKII. This unique crosstalk between CaMKII and Notch-1 pathways provides new insight into Notch signaling and potentially provides new targets for pharmacotherapeutics.
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PMID:Calcium/calmodulin-dependent kinase II regulates notch-1 signaling in prostate cancer cells. 1902 Nov 44


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