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PubMed1997

Experimentally induced changes in the endocytic traffic of P-glycoprotein alter drug resistance of cancer cells.

The MDR-1 gene product, plasma membrane glycoprotein or P-glycoprotein (PGP), has been shown to confer drug resistance to cancer cells by acting as an energy-dependent drug-efflux pump. We have examined the endocytic traffic of PGP in human multidrug-resistant cells and tested whether the traffic and the steady-state intracellular localization of PGP can be experimentally modulated. Here we show that 1) under steady state approximately 70% of cellular PGP is on the surface whereas approximately 30% is intracellular, 2) surface PGP undergoes constitutive endocytosis and recycling, 3) endocytosis of PGP involves clathrin and adaptin complex 2-dependent mechanism, and 4) PGP cycles through a Rab5-responsive endosomal compartment. Biochemical (such as antibody crosslinking of PGP or treatment of cells with chloroquine) and molecular (such as overexpression of Rab5) treatments were used to modulate the endocytic/ recycling traffic of PGP. Such treatments resulted in the redistribution of PGP from the cell surface to intracellular compartments. Cells with such "mislocalized" PGP showed a decrease in multidrug resistance, suggesting that clinically relevant strategies can be attempted by modulating PGP's temporal and spatial distribution within cancer cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Reduction of dietary obesity in aP2-Ucp transgenic mice: physiology and adipose tissue distribution.

We seek to determine whether increased energy dissipation in adipose tissue can prevent obesity. Transgenic mice with C57BL6/J background and the adipocyte lipid-binding protein (aP2) gene promoter directing expression of the mitochondrial uncoupling protein (UCP) gene in white and brown fat were used. Physiologically, UCP is essential for nonshivering thermogenesis in brown fat. Mice were assigned to a chow or a high-fat (HF) diet at 3 mo of age. Over the next 25 wk, gains of body weight were similar in corresponding subgroups (n = 6-8) of female and male mice: 4-5 g in chow nontransgenic and transgenic, 20 g in HF nontransgenic, and 9-11 g in HF transgenic mice. The lower body weight gain in the HF transgenic vs. nontransgenic mice corresponded to a twofold lower feed efficiency. Gonadal fat was enlarged, but subcutaneous white fat was decreased in the transgenic vs. nontransgenic mice in both dietary conditions. The results suggest that UCP synthesized from the aP2 gene promoter is capable of reducing dietary obesity.

Adaptor Protein Complex 2↗
PubMed2000

Internalization of proximal tubular type II Na-P(i) cotransporter by PTH: immunogold electron microscopy.

Physiological/pathophysiological alterations in proximal tubular P(i) reabsorption are associated with an altered brush-border membrane (BBM) expression of type II Na-P(i) cotransporter molecules. Reduction is achieved by an internalization and lysosomal degradation and an increase in P(i) reabsorption by new synthesis and BBM insertion of type II Na-P(i) cotransporters. In the present study, we investigated by immunohistochemistry and immunogold electron microscopy the routing of internalized rat type II Na-P(i) cotransporters (NaPi-2). In kidney of rats on a chronic low-P(i) diet, NaPi-2 is mainly localized in the BBM, in cisterns of the Golgi apparatus and sparsely also in large endocytotic vacuoles and lysosomes. Fifteen minutes after the injection of the 1-34 analog of parathyroid hormone (PTH), the amount of NaPi-2 was decreased in the BBM and increased in endocytotic vesicles. NaPi-2 molecules colocalized with horseradish peroxidase injected prior to the injection of PTH. Vesicles labeled for NaPi-2 were occasionally also labeled for clathrin or the adaptor protein AP2. We conclude that NaPi-2 molecules enter the subapical compartment from where NaPi-2-containing vesicles are segregated off and directed to the lysosomes. A clathrin-mediated pathway may contribute to the PTH-induced internalization of NaPi-2.

Adaptor Protein Complex 2↗
PubMed1998

PPARgamma induces the insulin-dependent glucose transporter GLUT4 in the absence of C/EBPalpha during the conversion of 3T3 fibroblasts into adipocytes.

To define the molecular mechanisms that control GLUT4 expression during adipogenesis, NIH-3T3 fibroblasts ectopically expressing different adipogenic transcription factors (C/EBPbeta, C/EBPdelta, C/EBPalpha, and PPARgamma) under the control of a tetracycline-responsive inducible (C/EBPs) or a constitutive retroviral (PPARgamma) expression system were used. Enhanced production of C/EBPbeta (beta2 cell line), C/EBPbeta together with C/EBPdelta (beta/delta39 cell line), C/EBPalpha (alpha1 cell line), or PPARgamma (Pgamma2 cell line) in cells exposed to dexamethasone and the PPARgamma ligand ciglitazone (a thiazolidinedione) resulted in expression of GLUT4 mRNA as well as other members of the adipogenic gene program, including aP2 and adipsin. Focusing our studies on the beta/delta39 cells, we have demonstrated that C/EBPbeta along with C/EBPdelta in the presence of dexamethasone induces PPARgamma, adipsin, and aP2 mRNA production; however, GLUT4 mRNA is only expressed in cells exposed to ciglitazone. In addition, enhanced expression of a ligand-activated form of PPARgamma in the beta/delta39 fibroblasts stimulates synthesis of GLUT4 protein and gives rise to a population of adipocytic cells that take up glucose in direct response to insulin. C/EBPalpha is not expressed in the beta/delta39 cells under conditions that stimulate the adipogenic program. This observation suggests that PPARgamma alone or in combination with C/EBPbeta and C/EBPdelta is capable of activating GLUT4 gene expression.

3T3 Cells↗
PubMed1996

cis-acting elements and trans-acting proteins in the transcription of chorionic gonadotropin/luteinizing hormone receptor gene in human choriocarcinoma cells and placenta.

We investigated the cis-acting elements and trans-acting proteins responsible for a higher basal rate of transcription of hCG/LH receptor gene in human choriocarcinoma JEG-3 cells compared with normal term pregnancy placenta. Sequential deletion of the 5'-flanking region of the gene revealed that there are three negative control regions (NCRs) designated NCR1 (-1457 to -1373 bp), NCR2 (-1051 to -835 bp), and NCR3 (-480 to -184 bp), and a promoter (-184 to -1 bp). NCR3 was more inhibitory than the other two; nearly 60-70% of the inhibitory activity resides in a sequence between -480 to -276 bp, and the rest resides in the sequence between -276 to -184 bp. Gel mobility shift assays showed that the nuclear extracts from JEG-3 cells contained proteins that form three complexes with NCR1, two with NCR2, and six with NCR3. Many of the proteins that form the complexes in NCR3 are shared with the other two NCRs. Most of the proteins that form these complexes are less abundant in nuclear extracts from JEG-3 cells than in those from placenta. The JEG-3 cell nuclear extracts also contained proteins that form three complexes with the proximal promoter of the hCG/LH receptor gene. These proteins were identified as Ap2, Ap2-like I, and Sp1 from the competition studies with synthetic excess unlabeled Ap2, Sp1, and CTF/NF1 consensus oligodeoxynucleotides and/or supershift in gel mobility assays with anti-Ap2 antibody. Although the JEG-3 cell nuclear extracts contained abundant Ap2-like protein I and low levels of Ap2 and Sp1 proteins, the placental nuclear extracts contained low levels of Ap2-like protein I and very low to nondetectable levels of Ap2 and Sp1 proteins. Deoxyribonuclease I footprinting revealed that the nuclear extracts from JEG-3 cells and placent protected the -116 to -93 bp and -65 to -45 bp regions in the proximal promoter of the hCG/LH receptor gene that contain Sp1 and Ap2 binding sites, respectively. However, the nuclear extracts from placenta only partially protected these regions, which is consistent with lower levels of proteins that bind to the proximal promoter of the gene. In summary, we conclude that the presence of low levels of proteins that bind to the NCRs and the high levels of proteins, especially Ap2-like I, that bind to the proximal promoter can potentially explain higher transcription of the hCG/LH receptor gene in JEG-3 cells compared with that in normal term pregnancy human placenta.

Adaptor Protein Complex 2↗
PubMed1998

Elevated connexin-43 expression in term human myometrium correlates with elevated c-Jun expression and is independent of myometrial estrogen receptors.

Just previous to the onset of parturition, a number of genes such as the one that codes for connexin-43 (Cx43) gap junction protein are induced in the myometrium. We have shown previously that activation of protein kinase C in human myometrial cultured cells leads to an up-regulation of cx43 transcription through an activating protein-1 element in the 5'-flanking promoter. Analyses were now performed on extracts of term myometrial tissue to test for an association between the up-regulation of cx43 expression and the expression of transcription factors and steroid hormone receptors that might regulate cx43 expression at term. Immunoblot analyses were performed on extracts of term myometrial tissue from women receiving elective or indicated cesarean sections to test for an association between the up-regulation of cx43 expression and the up-regulation of expression of the transcription factors c-Jun, c-Fos, and Sp1, which have cognate binding elements in the cx43 5'-flanking promoter. Immunoblot analysis, immunohistochemistry, and receptor binding assays were also performed to analyze the levels of progesterone receptors (PR) and estrogen receptors (ER) in the same term myometrial tissue, and these were compared to the levels in nonpregnancy myometrial tissue. The levels of PR were consistently 2- to 3-fold higher in term myometrial tissue than in nonpregnancy values and did not fluctuate during the menstrual cycle as did ER levels. Surprisingly, in term myometrium, ER was barely detectable by immunoblot and had whole cell diffuse staining by immunohistochemistry. In addition, very low levels of estrogen binding were observed in the term myometrial tissue. Treatment of primary myometrial cultures containing ER with estrogen for 3 or 48 h did not result in up-regulation of c-Jun or c-Fos proteins or in trans-activation from the proximal cx43 promoter with the activating protein-1 element. In contrast, an activated form of c-Jun protein was 10- to 18-fold higher in term myometrial tissue that also had elevated cx43 expression compared to c-Jun levels in term myometrial tissue with low cx43 expression. Likewise, c-Fos and Sp1 levels were 2-4 fold higher in term myometrial tissue with elevated cx43 expression. Although c-Fos and Sp1 proteins could be detected by immunoblot in myometrial tissue from nonpregnant women, c-Jun and Cx43 proteins could not. In summary, these results suggest that up-regulation of human myometrial cx43 gene expression at term involves induction of primarily c-jun expression through a mechanism that does not directly involve myometrial ER or the loss of PR. Peptide hormones that activate protein kinase cascades, such as the protein kinase C cascade, may be important to signal the onset of labor in humans.

Adaptor Protein Complex alpha Subunits↗
PubMed1994

Programming gene expression in developing epidermis.

As the major proteins of adult keratinocytes, keratins provide biochemical markers for exploring mouse epidermal embryogenesis. Here, we used a modified method of whole-mount in situ hybridization to track skin-specific expression of endogenous keratin mRNAs throughout embryogenesis. To monitor transcriptional regulation, we coupled this with beta-galactosidase expression of a human epidermal keratin promoter-driven transgene. These studies have radically changed our perception of how the program of gene expression becomes established during epidermal development. Specifically, we have discovered that (1) basal keratin (K5 and K14) genes are first detected at E9.5 in a highly regional fashion, and surprisingly as early as the single layered ectodermal stage; (2) the early patterns do not correlate with morphogenesis per se, but rather with regional variations in the embryonic origin of underlying mesenchyme, supporting morphogenetic criteria that early inductive cues are mesenchymal; (3) epidermal keratin genes are expressed in periderm, supporting the notion that this layer arises from ectodermal stratification, even though it is simple epithelial-like in morphology and is subsequently sloughed during development; (4) later embryonic patterns of K5 and K14 gene expression parallel proliferative capacity and not stratification; and (5) K1 and K10 mRNAs are first detected as early as E13.5, and their patterns correlate with differentiation and not stratification. These patterns of epidermal gene expression led us to explore whether potential transcriptional regulators of these genes are expressed similarly. We show that AP2 (but not Sp1) cRNAs hybridize in a pattern similar to, but preceding that of basal keratin cRNAs. Finally, using gene expression in cultured cells, we demonstrate that AP2 has a strong inductive effect on basal keratin expression in a cellular environment that does not normally possess AP2 activity.

Adaptor Protein Complex 2↗
PubMed1996

SHORT INTEGUMENT (SIN1), a gene required for ovule development in Arabidopsis, also controls flowering time.

The short integument (sin1) mutation causes a female-specific infertility, and a defect in the control of time to flowering in Arabidopsis. Female sterility of Sin- plants is due to abnormal ovule integument development and aberrant differentiation of the megagametophyte in a subset of ovules. An additional defect of sin1 mutants is the production of an increased number of vegetative leaf and inflorescence primordia leading to delayed flowering. The delayed flowering phenotype of sin1-1 is not due to a defect in the perception of day length periodicity or in gibberellic acid metabolism. Phenotypes of double mutant combinations of sin1 with terminalflower (tfl1) indicate that SIN1 activity is required for precocious floral induction typical in a tfl1 mutant. Unexpectedly, sin1-1 tfl1-1 plants do not make pollen, thus revealing a novel role for TFL1 in the anther. Early flowers of sin1-1 ap1-1 double mutants are transformed to long inflorescence-like shoots. A genetic model for the role of SIN1 in flowering time control is proposed.

Adaptor Protein Complex 1↗
PubMed1995

Expression and localization of alpha-adaptin isoforms.

There are two alpha-adaptin genes, alpha A and alpha C, which in brain encode proteins of of M(r) 108 x 10(3) and 104 x 10(3), respectively. Although both mRNAs can be detected on northern blots of brain and liver, the higher molecular mass polypeptide can only be detected on western blots of brain. Here we explain these observations by showing that alpha A is alternatively spliced and that the protein product in most tissues is different from the one expressed in brain in that it is missing 21 amino acids within the hinge region, giving it a similar mobility to that of alpha C. Monospecific antibodies were raised against the various alpha-adaptin isoforms and used to compare their distribution in cells and tissues. Both alpha A and alpha c are co-assembled into the same coated pits, and the larger isoform of alpha A is co-assembled with the smaller isoforms of alpha-adaptin, both in cells that naturally express it an in transfected cells. Examination of brain and spinal cord sections, labelled either for the larger isoform of alpha A or for alpha C, reveals that that the two are to some extent differentially distributed, consistent with previous in situ hybridisation studies. This finding, combined with the observation that there is considerable variability in the relative expression of the two isoforms in different tissues, indicates that the two genes are switched on in response to different stimuli. Moreover, the larger isoform of alpha A appears to be more efficiently concentrated in the nerve terminals than alpha C, which is found not only at the terminals but also diffusely distributed in the cell bodies and dendrites. This suggests that alpha C may play more of a role in the recycling of membrane components throughout the cell.

3T3 Cells↗
PubMed1996

A membrane-associated protein complex with selective binding to the clathrin coat adaptor AP1.

Adaptors are the membrane-binding components of clathrin-coated vesicles. The interaction of the trans-Golgi coat adaptor AP1 with membrane-associated proteins was analyzed by affinity chromatography. Proteins of 83 and 52 kDa bound specifically to the core domain of AP1 and showed no interaction with AP2 or other clathrin-coated vesicle proteins. The AP1-binding proteins were tightly membrane-associated, though behaved as peripheral membrane proteins. They were detected in membranes depleted of clathrin-coated vesicles and not in coated vesicles, suggesting that the interaction of these proteins with AP1 may precede coated vesicle budding. Co-fractionation of the AP1-binding proteins with trans-Golgi network membrane was also observed. Upon gel filtration, both AP1-binding proteins eluted in a high molecular mass complex which was labile at high concentrations of Tris. The 83 kDa protein bound to AP1 affinity resin in the absence of the 52 kDa protein. In contrast, the separated 52 kDa protein did not bind AP1, suggesting that the 83 kDa protein is the AP1-binding component of the complex. Characterization of this protein complex defines a novel membrane-associated component that specifically interacts with AP1 and may contribute to its function in forming clathrin-coated vesicles.

Adaptor Protein Complex 1↗
PubMed1999

The Drosophila GMII gene encodes a Golgi alpha-mannosidase II.

In this paper we show the organisation of the Drosophila gene encoding a Golgi alpha-mannosidase II. We demonstrate that it encodes a functional homologue of the mouse Golgi alpha-mannosidase II. The Drosophila and mouse cDNA sequences translate into amino acid sequences which show 41% identity and 61% similarity. Expression of the Drosophila GMII sequence in CHOP cells produces an enzyme which has mannosidase activity and is inhibited by swainsonine and by CuSO(4.) In cultured Drosophila cells and in Drosophila embryos, antibodies raised against a C-terminal peptide localise this product mainly to the Golgi apparatus as identified by cryo-immuno electron microscopy studies and by antibodies raised against known mammalian Golgi proteins. We discuss these results in terms of the possible use of dGMII as a Drosophila Golgi marker.

Adaptor Protein Complex alpha Subunits↗
PubMed1999

Differential distribution of mannose-6-phosphate receptors and furin in immature secretory granules.

In neuroendocrine cells sorting of proteins from immature secretory granules (ISGs) occurs during maturation and is achieved by clathrin-coated vesicles containing the adaptor protein (AP)-1. We have investigated the role of the mannose-6-phosphate receptors (M6PRs) in the recruitment of AP-1 to ISGs. M6PRs were detected in ISGs isolated from PC12 cells by subcellular fractionation, and by immuno-EM labelling on cryosections. In light of our previous results, where greater than 80% of the ISGs were found to contain furin, we examined the relationship between furin and M6PR on ISGs. By immunoisolation techniques we find that 50% at most of the ISGs contain the cation-independent (CI)-M6PR. Using sequential immunoisolation we could demonstrate that there are two populations of ISGs: those that have both M6PR and furin, and those which contain only furin. Furthermore, using immobilized GST-fusion proteins containing the cytoplasmic domain of the CI-M6PR we have shown binding of AP-1 requires casein kinase II phosphorylation of the CI-M6PR fusion protein, and in particular phosphorylation of Ser(2474). Addition of these phosphorylated GST-CI-M6PR fusion proteins to a cell-free assay reconstituting AP-1 binding to ISGs inhibits AP-1 recruitment to ISGs.

3T3 Cells↗
PubMed1999

The majority of clathrin coated vesicles from lactating rabbit mammary gland arises from the secretory pathway.

Clathrin coated vesicles were isolated from lactating rabbit mammary gland by differential centrifugation, centrifugation on (2)H2O-sucrose cushions and Sephacryl S-1000 chromatography. Mammary epithelial cells contain an unexpectedly high quantity of clathrin coated vesicles which appear heterogeneous in size, with a mean diameter of 95.9+/-10.5 nm and a density of 1.23 g x ml(-1). Analysis of clathrin coated vesicle adaptor composition by SDS-PAGE and western blot showed that only approximately 5-10% of total APs consist of AP-2 in isolated mammary gland clathrin coated vesicles whereas it represents approximately 70% of the total APs from bovine brain clathrin coated vesicles. Cargo molecules known to be transcytosed such as IgG, IgA, and the pIgR were detected in the clathrin coated vesicles, indicating that part of this vesicle population is involved in transcytotic pathways. However, as the vast majority of the clathrin coated vesicles contained AP-1, it was likely that these clathrin coated vesicles were involved in the secretory pathway. Relatively high quantities of furin and cation-independent mannose 6-phosphate receptor were detected in mammary clathrin coated vesicles. By immuno electron microscopy, AP-1 and the cation-independent mannose 6-phosphate receptor were localized in Golgi-associated vesicles and on the membrane of secretory vesicles. The presence of AP-1 in the coat patches on the membrane of secretory vesicles containing casein micelles, and the presence of alpha(s1)-casein in mammary gland clathrin coated vesicles, support a role for AP-1 in the maturation of secretory vesicles. Our data pinpoint the importance of clathrin coated vesicles in lactating mammary epithelial cells, and suggest these vesicles are involved in the transcytotic pathway, in sorting at the trans-Golgi network and in the biogenesis of casein-containing secretory vesicles.

Adaptor Protein Complex alpha Subunits↗
PubMed1999

Association of AP1 adaptor complexes with GLUT4 vesicles.

Nycodenz gradients have been used to examine the in vitro effects of GTP-(gamma)-S on adaptor complex association with GLUT4 vesicles. On addition of GTP-(gamma)-S, GLUT4 fractionates as a heavier population of vesicles, which we suggest is due to a budding or coating reaction. Under these conditions there is an increase in co-sedimentation of GLUT4 with AP1, but not with AP3. Western blotting of proteins associated with isolated GLUT4 vesicles shows the presence of high levels of AP1 and some AP3 but very little AP2 adaptor complexes. Cell free, in vitro association of the AP1 complex with GLUT4 vesicles is increased approximately 4-fold by the addition of GTP-(gamma)-S and an ATP regenerating system. Following GTP-(gamma)-S treatment in vitro, ARF is also recruited to GLUT4 vesicles, and the temperature dependence of ARF recruitment closely parallels that of AP1. The recruitment of both AP1 and ARF are partially blocked by brefeldin A. These data demonstrate that the coating of GLUT4 vesicles can be studied in isolated cell-free fractions. Furthermore, at least two distinct adaptor complexes can associate with the GLUT4 vesicles and it is likely that these adaptors are involved in mediating distinct intracellular sorting events at the level of TGN and endosomes.

Adaptor Protein Complex 1↗
PubMed1999

Inhibition of clathrin-coated pit assembly by an Eps15 mutant.

Recent data have shown that Eps15, a newly identified component of clathrin-coated pits constitutively associated with the AP-2 complex, is required for receptor-mediated endocytosis. However, its precise function remains unknown. Interestingly, Eps15 contains three EH (Eps15-Homology) domains also found in proteins required for the internalization step of endocytosis in yeast. Results presented here show that EH domains are required for correct coated pit targeting of Eps15. Furthermore, when cells expressed an Eps15 mutant lacking EH domains, the plasma membrane punctate distribution of both AP-2 and clathrin was lost, implying the absence of coated pits. This was further confirmed by the fact that dynamin, a GTPase found in coated pits, was homogeneously redistributed on the plasma membrane and that endocytosis of transferrin, a specific marker of clathrin-dependent endocytosis, was strongly inhibited. Altogether, these results strongly suggest a role for Eps15 in coated pit assembly and more precisely a role for Eps15 in the docking of AP-2 onto the plasma membrane. This hypothesis is supported by the fact that a GFP fusion protein encoding the ear domain of (alpha)-adaptin, the AP-2 binding site for Eps15, was efficiently targeted to plasma membrane coated pits.

Adaptor Protein Complex alpha Subunits↗
PubMed1994

Microtubule reorganization and lysosome redistribution by a viral v-src oncogene, in mouse Balb/3T3 cells expressing human EGF receptor.

The epidermal growth factor (EGF)-induced endocytosis of its receptor is an obligatory pathway for the cellular regulation of the EGF-specific receptor (EGF-R). BNER4 is a mouse Balb/3T3 cell line transfected with human EGF-R complementary DNA (cDNA). B4/src-13 and B4/src-24 are BNER4 cells transfected with a viral oncogene v-src. Indirect immunofluorescence study demonstrated that EGF-R was mostly localized at the perinuclear region in BNER4 cells at 60 min after EGF addition, whereas it was diffusely distributed throughout the cytoplasm in its v-src transfectants. Double indirect immunofluorescence study further confirmed that EGF-R was localized in lysosomes in BNER4 and B4/src-13 cells at 60 min after EGF addition. Intracellular distribution of the Golgi apparatus, clathrin-coated vesicles and early endosomes were similar in all cell lines. However, the lysosomes detected by anti-lysosomal membrane protein (LGP85) antibodies were diffusely distributed throughout the cytoplasm in the v-src transfectacts. By contrast, in the parental BNER4 cells, the lysosomes were mostly localized in the perinuclear region. The organization of microtubules, but not of actin, was markedly different between BNER4 cells and its v-src transfectants. Nocodazole, which depolymerizes microtubules, altered the distribution of the lysosomes and EGF-R in BNER4 cells. Both intracellular lysosome distribution and microtubule organization in nocodazole-treated BNER4 cells were found to be similar to those in its v-src transfectants without nocodazole treatment. These findings support the notion that changes in lysosome distribution may be correlated with microtubule reorganization by v-src in mouse Balb/3T3 cells.

3T3 Cells↗
PubMed2000

Heterogeneity of therapeutic responses in asthma.

Asthma is a complex clinical syndrome with multiple genetic and environmental factors contributing to its phenotypic expression. This aetiological heterogeneity adds to the complexity when addressing variation in the response to anti-asthma treatment. Currently, there are three main lines of treatment available: (i) inhaled glucocorticoids which have multiple mechanisms of action; (ii) beta 2-agonists which are very effective bronchodilators and act predominantly on airway smooth muscle; and (iii) cysteinyl-leukotriene inhibitors. Analysis of the repeatability (r) of the treatment response, defined as the fraction of the total population variance which results from among-individual differences, shows values of r between 60-80% indicating that a substantial fraction of the variance of the treatment response could be genetic in nature. Among the sources of variability that could contribute to the observed heterogeneity in the response to treatment are the degree of underlying inflammation, such as in glucocorticoid resistance, and polymorphisms in the genes encoding the drug target, such as beta 2-adrenoceptor and 5-lipoxygenase.

Adaptor Protein Complex alpha Subunits↗