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- Table of Contents
Facts about Adenylyl cyclase-associated protein 1.
Human | |
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Gene Name: | CAP1 |
Uniprot: | Q01518 |
Entrez: | 10487 |
Belongs to: |
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CAP family |
adenylyl cyclase-associated protein 1; CAP, adenylate cyclase-associated protein 1 (yeast); CAP1; CAP1-PEN; CAPCAP 1; SSKAP55
Mass (kDA):
51.901 kDA
Human | |
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Location: | 1p34.2 |
Sequence: | 1; NC_000001.11 (40040065..40072649) |
Cell membrane; Peripheral membrane protein.
The CAP1 structure is an immunodominant epitope on the CEA molecule. Utilizing a non-antagonistic CAP1-6D protein, scientists can choose a specific group of human CTL. This peptide can perform probar and selective tasks of CAP1.
One of the most effective targets for immunotherapy for cancer is the human carcinoembryonic Antigen (CEA). The CEA molecule has been shown to be overexpressed within a number of human tumors, making it a promising candidate for clinical applications. A saccharomyces cerevisiae vector with an CEA transgene stimulates human dendritic cells and elicits T-cell responses that are CEA specific. The activation of human cells by a yeast-CEA vector results in an increase in the expression of the surface of CD80 and CD54, MHC class II and IL-8.
PV-CEA pseudoviruses encode CEA without a signal peptide. This alteration could affect CEA protein synthesizing, modification, and degradation, as and antigen processing pathways. It can also display human A2-restricted epitopes. This epitope, referred to as CAP1 was used to evaluate mucosal as well as systemic CTL responses in A2-Tg mice.
The CAP1 Peptide has also been modified to become more immunogenic. In particular, the amino acid residue 6 of the CAP1 peptide can be substituted with aspartic acid. These modifications enhance CTL recognition. This is not due to an increased HLA-A2.1 binding capacity. This effect is believed to be due to the activation of TCR. The CEA-expressing T-cell line was capable of lysing human tumor cells.
TNFa is produced when CEA-specific CTL are stimulated by CAP1 propeptide. CEA-specific CTL produce TNFa when stimulated with high levels of CAP1. These results suggest that CEA-specific CTLs have a role to play in removal of tumors.
In addition to the CAP1 protein, CEA protein is also expressed in living cells. When inoculated by PV-CEA pseudoviruses and CEA-expressing cells, they generate an anti CAP1 immune response in mice. The cells also respond to PV-IL-2 through the expression of CAP-1-specific CTLs when CEA pseudoviruses are administered simultaneously.
GM-CSF production in mice stimulated with CAP1 the peptide has been proven to increase after 24 hours. The peptides CAP1-6D generate approximately 9,000 pg/ml of GM-CSF in mice when stimulated with 0.2 mg/ml. These results are consistent with previous human studies.
Recent research has shown that an analog peptide CAP1-6D is able to select a specific subset of human CTL from CAP1. This peptide can be utilized in live to select a subset of human CTL. CAP1 Ligands are partial antagonists that selectively stimulate certain T cells' functions. However, we have found that biologically natural CAP1 has more partial agonist properties than altered peptides.
Our results demonstrated that a CEA-specific CTL subset produced high levels GM-CSF and g-IFN when stimulated with the peptide CAP1-6D. The corresponding IL-4, IL-10 levels were extremely low when stimulated with the CAP1-specific CTL. These results suggest that an CEA specific peptide might select a subset of human CTL subsets that are specifically targeting CEA.
Another way to identify CD8+ T cells that target cancers that express CEA was to alter the CEA epitope and replace the amino acid six-position residue with aspartic acid. Interestingly, this strategy did not improve the binding affinity of CTLs to the HLA-A2.1 antigen, but increased their ability to recognize the CAP1-derived protein. Furthermore, these T-cell lines could lyse cancer cells expressing CEA.
The same method was employed to successfully isolate peptide specific CTL (from CAP1) using an fused of peptide. The peptide was loaded into APCs, and later introduced into the individual. The antigenic peptide binds to the APC. Thus, this process is regarded as autologous. The peptide initiates a CTL immune response.
To determine the AA residues found in human proteins, we used an T cell line that has the H3.3 K27M epitope. We were able create a phenotype-specific human CTL response using this particular composition. These results also show how the use of immunotherapy targeting an epitope can affect a particular population of cells.
CTL from the T-15 strain also produce CAP1-specific T cells. These cells lysed human cancerous cells that expressed native CEA and stimulated the production of GM CSF, g-IFN, TNFa, and IL-2. This peptide may be beneficial in the treatment of tumors that are CEA positive.
Recent studies have demonstrated that the peptide CAP1-6D, derived from human CEA is able to enhance CTL recognition of tumor cells in an restricted manner by HLA-A2. To enhance the immunogenicity of the CAP1 the peptide, a new enhancer agonist was discovered. The agonist peptide was predicted that it will bind to CTL's TCR and be more sensitive to cells of the target than CAP1 which is the cognate antibody.
T-cells were grown using T-15-CAP1 and CAP1-6D, both from patients with metastatic carcinoma. Both peptides were extracted from T-cell cultures and then stimulated with autologous DC pulsed with CAP1 peptide or an agonist, CAP1-6D. The IVS cycles corresponding to the IVS cycles were analyzed for differences in the production of IFN-g.
The peptide CAP1-6D stimulated the T-N2 CTL to produce GIFN. The highest g-IFN production was stimulated by the highest dose of CAP1 (20mg/ml) after 24 hours. After 48 hours, gIFN levels start to decrease. However, both peptides produce IL-2, gIFN, and GM-CSF.
It is also an effective anti-inflammatory peptide. The peptide stimulates T-Vac8 cells to produce G-IFN. However, this effect is only visible at the highest dose of CAP1-6D. T-Vac8 cells reacted to CAP1-6D and produced little to no IL-4 and IL-10 after stimulation with the peptide.
The T-N2 CTL in CAP1-6D is stimulated to produce GM-CSF in just 24 hours of the culture. The peptide is dose-dependent and requires 50-100 times less the concentration of peptides to produce half-maximal GM CSF. In experiments, CAP1-6D stimulates T-N2 CTL to produce GM-CSF in an autonomous epidermal cell manner.
CAP1-6D is an effective anti-inflammatory agent that has pleiotropic properties. It is the homologue of human prostasin and is expressed at high levels in the prostate gland. The skin also has the CAP1 protein which is vital to protect the epidermis. Serine proteases that are bound to membranes are capable of inducing cell signalling by activating the proteinase receptor family.
In in vitro stimulation of T cells through CAP1-6D. This process has not been validated in other systems of experimentation. The peptide may decrease the exhaustion rate of T cells when they are stimulated. It's unclear, but preliminary studies suggest that the CAP1-6D peptide could have an effect on anti-tumor activity. The potential for its clinical use is in its ability to induce anti-inflammatory effects.
CAP1-6D is a peptide which acts as an agonist to activate CTL of multiple donors. The agonist CAP1-6D activated the CTL of multiple donors expressing -A2 (human antigen of cytotoxic lymphocytes). The peptide is recognized by T-Vac8 as well as T-Vac24 T-cells, which use different segments of the TCR GEN. The CAP1-6D peptide may also bind to different T-cell receptors so it can act as an antagonist.
The CAP1-6D peptide has been tested in both experimental and clinical settings. This peptide is able to stimulate CTL from PBMC and has both specific peptide reactivity aswell being a citotoxic agent. Its specificity and the sensitivity of this peptide make it a viable indicator for detecting CTL. More research is required to determine whether this peptide can be used in clinical trials for patients.
The CAP1-6D peptide is a highly effective protein that is able to detect CAP1. It is much more efficient than CAP-1. It is capable of detecting up to 10 times the amount of lymphocytes as CAP-1. Its efficacy ranges between 10-2 and 10-3 ug/ml. It is also stable and is suitable for use in immunohistochemical tests.
To increase the effectiveness of CAP1, another method is to introduce a peptide antagonistic CAP1 to enhance its immunogenicity. The peptide was discovered to be more effective than CAP1 as an CTL effector in combination with T-Vac8. The CAP1-6D peptide is more sensitive to target cells than CAP1 when used in conjunction with CEA.
CEA antagonists can be utilized to treat solid tumors. The peptides utilized by CEA antagonists hinder the growth of cancerous cells, and also destroy cells that express CEA. In addition to this it is believed that the CAP1 protein has a positive impact on the immune system. Studies involving mixed lymphocyte tumor cells have demonstrated its immunogenicity.
The CAP1-6D protein is produced from natural CAP1 or CTL. Using a combination of these two types of peptides the CAP1-6D antibody recognizes tumor cells with endogenous CEA, HLA-A2, SW480, and SW1463. The peptide also recognizes tumor cells that express endogenous CEA when they are co-expressed in combination with g-IFN and gamma-IFN.
PMID: 1406678 by Matviw H., et al. Identification of a human cDNA encoding a protein that is structurally and functionally related to the yeast adenylyl cyclase- associated CAP proteins.
PMID: 16807684 by Beranova-Giorgianni S., et al. Phosphoproteomic analysis of the human pituitary.