Disease relevance of PCP4

• To further characterize PCP4 and its possible contribution to cerebellar hypoplasia in trisomy 21, or Down Syndrome (DS), we cloned and sequenced the full length human cDNA, isolated a YAC which carries the entire gene, determined the gene structure, and characterized its expression [1].
• PEP-19 overexpression in human uterine leiomyoma [2].
• PCP4 is up-regulated in aldosterone producing adenomas (APA) of the human adrenal cortex, and its expression levels are directly correlated to those of aldosterone synthase (CYP11B2) in those tumors [3].
• Protein levels of PCP4 are also up-regulated in idiopathic hyperaldosteronism (IHA) cases, when evaluated through H-score after immunohistochemical analysis [3].
• The messenger RNA levels of PCP4 are directly correlated to mutations in the KCNJ5 potassium channel gene in human adrenocortical tumors. KCNJ5 mutations are directly related to plasmatic aldosterone concentration (PAC) in APA patients, which makes PCP4 levels indirectly correlated to aldosterone levels in human subjects [3].

Psychiatry related information on PCP4

• PEP-19 immunohistochemistry defines the basal ganglia and associated structures in the adult human brain, and is dramatically reduced in Huntington's disease [4].
• Preliminary data from immunoblotting experiments indicate that PEP-19 immunoreactivity is significantly reduced in cerebellum in Alzheimer's disease [4].

High impact information on PCP4

• Nine were fragments of hemoglobin, and the remainder included two species of calmodulin, two of myelin basic protein, and one each of 67 kDa neurofilament protein and PEP-19 [5].
• Furthermore, mutant mice showing degeneration of Purkinje cells exhibit markedly decreased levels of PEP-19 [6].
• Immunochemical and immunohistochemical techniques were used to map the tissue distribution and cellular localization of a rat brain-specific polypeptide, termed PEP-19 [6].
• The reduction in PEP-19 immunoreactivity in Alzheimer's disease and Huntington's disease suggests that PEP-19 may play a role in the pathophysiology of these diseases through a mechanism of calcium/calmodulin disregulation [4].
• While there were no apparent alterations of immunoreactivity in Down's syndrome or in Parkinson's disease, immunohistochemical analysis showed a massive loss of PEP-19 immunoreactivity in the caudate nucleus, putamen, globus pallidus and substantia nigra in Huntington's disease [4].
• The knockdown of PCP4 in the human adrenocortical cell line H295R with siRNA produced a significant decrease in angiotensin-II induced aldosterone production [3].
• Several findings in human adrenocortical tissues suggest that PCP4 can work in conjunction with calmodulin (CaM) in order to activate the CREB transcription factor in the nucleus [3].

Biological context of PCP4

• PCP4 maps between D21S345 and P31P10SP6 on chromosome 21q22.2-->q22.3 [7].
• Molecular genetic characterization and comparative mapping of the human PCP4 gene [1].
• The novel rat-specific protein, tentatively named long PEP19 isoform (LPI), is the product of alternative splicing of the rat PCP4 gene encoding PEP19 [8].
• PCP4 is highly expressed in ectoderm and particularly in neuroectoderm derivatives during mouse embryogenesis [9].
• It is also presently unknown whether overexpression of the PEP-19 gene is involved in certain phenotypes of Down syndrome [10].

Anatomical context of PCP4

• 5. At E10.5, PCP4 shows a strong signal in the post-mitotic cells of the diencephalon, the metencephalon and the myelencephalon and in the dorsal and cranial ganglia [9].
• At E17.5, PCP4 is expressed in the central nervous system, in the myenteric plexus, and in other ectoderm derivatives, for instance the lens, the hairy cells of the cochlea, the enamel organ and the hair follicles [9].
• Immunohistochemistry for PEP-19 appears to define the basal ganglia and related structures [4].
• The substantia nigra and both segments of the globus pallidus showed PEP-19 immunoreactivity only in the neuropil [4].
• The strongest immunoreactivity is seen in the caudate nucleus and putamen, each of which showed both cell body and neuropil PEP-19 immunoreactivity [4].
• PCP4 is localized in the zona glomerulosa (ZG) of the non-pathological and hyperplastic human adrenal cortex [3].

Associations of PCP4 with chemical compounds

• Truncated camstatin is selectively phosphorylated by four isoforms of protein kinase C. Furthermore, treatment of full-length PEP-19 with PKCgamma catalyzes phosphorylation of the same serine residue [11].
• Through measurements on the respective methylethers (anisoles) the O-H bond of 2,4,6-TCP turns out to be 5 kcal/ mol, and that in PCP 4 kcal/mol, less strong than O-H in phenol itself [12].

Other interactions of PCP4

• Among the genes identified, decreased expressions of NEFH and PCP4/PEP19 were further examined [13].
• While most of the abnormal neurons in the lesion appear to be derived from granule cells, several Purkinje cell specific polyclonal and monoclonal antibodies, including L7, PEP 19 and calbindin, labeled a minor subpopulation [14].
• We report the identification of a cDNA that encodes a putative protein of 94 amino acids and expected molecular weight of 10.7 kDa, the C-terminal half of which is identical to that of PEP19, a small, brain-specific protein involved in Ca++/calmodulin signaling [8].
• We found that antibodies raised against the first 13 N-terminal amino acids of LPI, not present in PEP19, recognize a protein enriched in the developing rat brain [8].

Analytical, diagnostic and therapeutic context of PCP4

• Murine PCP4 expression in the brain has been detected by Northern blot analysis to be mainly post-natal and in the adult to have a neuronal pattern [9].
• The H(alpha) chemical shifts and the circular dichroism spectra of the camstatins are consistent with those of "nascent helices". We submit that PEP-19 is a PKC substrate, and that the phosphorylation state of PEP-19 may play a role in the modulation of calmodulin-dependent signaling [11].

References