P11

Effect of Maternal +/-Citalopram Exposure on P11 Expression and Neurogenesis in the Mouse Fetal Brain.[Pubmed:28076682]

ACS Chem Neurosci. 2017 May 17;8(5):1019-1025.

Fetal exposure to selective serotonin reuptake inhibitors (SSRI) has been associated with increased risk of adverse neurodevelopmental outcomes. In the adult brain, SSRI therapy regulates P11 (s100a10) expression and alters neurogenesis. The protein P11 indirectly regulates 5-HT signaling through 5-HT1B/D receptors. In the fetal brain, signaling through these receptors modulates axonal circuit formation. We determined whether P11 is expressed in the fetal mouse brain, and whether maternal SSRI exposure affects fetal P11 expression and neurogenesis. The SSRI +/- citalopram was administered to pregnant mice from gestational day 8 to 17. Results show that P11 is expressed in fetal thalamic neurons and thalamocortical axons. Furthermore, P11 protein expression is significantly decreased in the fetal thalamus after in utero +/-citalopram exposure compared to untreated controls, and neurogenesis is significantly decreased in specific fetal brain regions. These findings reveal differential regulation of P11 expression and altered neurogenesis in the fetal brain as a result of maternal SSRI exposure.

Alterations of p11 in brain tissue and peripheral blood leukocytes in Parkinson's disease.[Pubmed:28137881]

Proc Natl Acad Sci U S A. 2017 Mar 7;114(10):2735-2740.

Individuals with Parkinson's disease (PD) often suffer from comorbid depression. P11 (S100A10), a member of the S100 family of proteins, is expressed widely throughout the body and is involved in major depressive disorder and antidepressant response. Central P11 levels are reduced in postmortem tissue from depressed individuals; however, P11 has not yet been investigated in PD patients with depression or those without depression. We investigated P11 levels in postmortem PD brains and assessed whether peripheral P11 levels correlate with disease severity. Substantia nigra, putamen, and cortical P11 protein levels were assessed in postmortem brain samples from PD patients and matched controls. In a different set of postmortem brains, P11 mRNA expression was measured in dopaminergic cells from the substantia nigra. Both P11 protein and mRNA levels were decreased in PD patients. Peripheral P11 protein levels were investigated in distinct leukocyte populations from PD patients with depression and those without depression. Monocyte, natural killer (NK) cell, and cytotoxic T-cell P11 levels were positively associated with the severity of PD, and NK cell P11 levels were positively associated with depression scores. Given that inflammation plays a role in both PD and depression, it is intriguing that peripheral P11 levels are altered in immune cells in both conditions. Our data provide insight into the pathological alterations occurring centrally and peripherally in PD. Moreover, if replicated in other cohorts, P11 could be an easily accessible biomarker for monitoring the severity of PD, especially in the context of comorbid depression.

Mantle cell lymphoma with a novel t(11;12)(q13;p11.2): a proposed alternative mechanism of CCND1 up-regulation.[Pubmed:28132860]

Hum Pathol. 2017 Jun;64:207-212.

Mantle cell lymphoma (MCL) is typically characterized by t(11;14), which places the IGH@ enhancer elements upstream of CCND1. This fusion results in up-regulation of CCND1 and consequently its protein product cyclin D1. Recent studies have shown that in MCL, mutations or translocations occurring within the 3' untranslated region (UTR) of the CCND1 gene can result in a truncated mRNA transcript that is more stable and associated with more aggressive disease. We identified a case of MCL showing cyclin D1 overexpression by immunohistochemistry and a t(11;12)(q13;P11.2) by conventional cytogenetic studies. Next-generation genomic sequencing indicated a chromosomal break through the CCND1 3'-UTR and fusion with a non-coding region of chromosome 12. We suggest that, in the absence of the typical CCND1/IGH@ fusion, this rearrangement promotes MCL pathogenesis by eliminating miRNA interaction elements within the 3'-UTR of the CCND1 mRNA transcript consequently resulting in CCND1 overexpression.

Pharmacoproteomic analysis of a novel cell-permeable peptide inhibitor of tumor-induced angiogenesis.[Pubmed:21558493]

Mol Cell Proteomics. 2011 Aug;10(8):M110.005264.

P11, a novel peptide ligand containing a PDZ-binding motif (Ser-Asp-Val) with high affinity to integrin alpha(v)beta(3) was identified from a hexapeptide library (PS-SPCL) using a protein microarray chip-based screening system. Here, we investigated the inhibitory mechanism of P11 (HSDVHK) on tumor-induced angiogenesis via a pharmacoproteomic approach. P11 was rapidly internalized by, human umbilical vein endothelial cells (HUVECs) via an integrin alpha(v)beta(3)-mediated event. Caveolin and clathrin appeared to be involved in the P11 uptake process. The cell-penetrating P11 resulted in suppression of bFGF-induced HUVEC proliferation in a dose-dependent manner. Phosphorylation of extracellular-signal regulated kinase (ERK1/2) and mitogen-activated protein kinase kinase (MEK) in bFGF-stimulated HUVECs was inhibited by cell-permeable P11. Proteomic analysis via antibody microarray showed up-regulation of p53 in P11-treated HUVECs, resulting in induction of apoptosis via activation of caspases-3, -8, and -9. Several lines of experimental evidence strongly suggest that the molecular mechanism of P11, a novel anti-angiogenic agent, inhibits bFGF-induced HUVEC proliferation via mitogen-activated protein kinase kinase and extracellular-signal regulated kinase inhibition as well as p53-mediated apoptosis related with activation of caspases.

Site-specific inhibition of integrin alpha v beta 3-vitronectin association by a ser-asp-val sequence through an Arg-Gly-Asp-binding site of the integrin.[Pubmed:19882657]

Proteomics. 2010 Jan;10(1):72-80.

A functional proteomic technology using protein chip and molecular simulation was used to demonstrate a novel biomolecular interaction between P11, a peptide containing the Ser-Asp-Val (SDV) sequence and integrin alpha v beta 3. P11 (HSDVHK) is a novel antagonistic peptide of integrin alpha v beta 3 screened from hexapeptide library through protein chip system. An in silico docking study and competitive protein chip assay revealed that the SDV sequence of P11 is able to create a stable inhibitory complex onto the vitronectin-binding site of integrin alpha v beta 3. The Arg-Gly-Asp (RGD)-binding site recognition by P11 was site specific because the P11 was inactive for the complex formation of a denatured form of integrin-vitronectin. P11 showed a strong antagonism against alpha v beta 3-GRGDSP interaction with an IC(50) value of 25.72+/-3.34 nM, whereas the value of GRGDSP peptide was 1968.73+/-444.32 nM. The binding-free energies calculated from the docking simulations for each P11 and RGD peptide were -3.99 and -3.10 kcal/mol, respectively. The free energy difference between P11 and RGD corresponds to approximately a 4.5-fold lower K(i) value for the P11 than the RGD peptide. The binding orientation of the docked P11 was similar to the crystal structure of the RGD in alpha v beta 3. The analyzed docked poses suggest that a divalent metal-ion coordination was a common driving force for the formation of both SDV/alpha v beta 3 and RGD/alpha v beta 3 complexes. This is the first report on the specific recognition of the RGD-binding site of alpha v beta 3 by a non-RGD containing peptide using a computer-assisted proteomic approach.

High-throughput screening of novel peptide inhibitors of an integrin receptor from the hexapeptide library by using a protein microarray chip.[Pubmed:15634795]

J Biomol Screen. 2004 Dec;9(8):687-94.

Protein microarray is an emerging technology that makes high-throughput analysis possible for protein-protein interactions and analysis of proteome and biomarkers in parallel. The authors investigated the application of a novel protein microarray chip, ProteoChip, in new drug discovery. Integrin alpha(v)beta(3) microarray immobilized on the ProteoChip was employed to screen new active peptides against the integrin from multiple hexapeptide sublibraries of a positional scanning synthetic peptide combinatorial library (PS-SPCL). The integrin alpha(v)beta(3)-vitronectin interaction was successfully demonstrated on the integrin microarray in a dose-dependent manner and was inhibited not only by the synthetic RGD peptide but also by various integrin antagonists on the integrin microarray chip. Novel peptide ligands with high affinity to the integrin were also identified from the peptide libraries with this chip-based screening system by a competitive inhibition assay in a simultaneous and high-throughput fashion. The authors have confirmed antiangiogenic functions of the novel peptides thus screened through an in vitro and in vivo angiogenesis assay. These results provide evidence that the ProteoChip is a promising tool for high-throughput screening of lead molecules in new drug development.