Role of T198 Modification in the Regulation of p27Kip1 Protein Stability and Function

The tumor suppressor gene p27Kip1 plays a fundamental role in human cancer progression. Its expression and/or functions are altered in almost all the different tumor histotype analyzed so far. Recently, it has been demonstrated that the tumor suppression function of p27 resides not only in the ability to inhibit Cyclins/CDKs complexes through its N-terminal domain but also in the capacity to modulate cell motility through its C-terminal portion. Particular interest has been raised by the last amino-acid, (Threonine 198) in the regulation of both protein stability and cell motility

Novel mutations in natriuretic peptide receptor-2 gene underlie acromesomelic dysplasia, type maroteaux

<p>Abstract</p> <p>Background</p> <p>Natriuretic peptides (NPs) are peptide hormones that exert their biological actions by binding to three types of cell surface natriuretic peptide receptors (NPRs). The receptor NPR-B binding C-type natriuretic peptide (CNP) acts locally as a paracrine and/or autocrine regulator in a wide variety of tissues. Mutations in the gene <it>NPR2</it> have been shown to cause acromesomelic dysplasia-type Maroteaux (AMDM), an autosomal recessive skeletal disproportionate dwarfism disorder in humans.</p> <p>Methods</p> <p>In the study, presented here, genotyping of six consanguineous families of Pakistani origin with AMDM was carried out using polymorphic microsatellite markers, which are closely linked to the gene <it>NPR2</it> on chromosome 9p21-p12. To screen for mutations in the gene <it>NPR2</it>, all of its coding exons and splice junction sites were PCR amplified from genomic DNA of affected and unaffected individuals of the families and sequenced.</p> <p>Results</p> <p>Sequence analysis of the gene <it>NPR2</it> identified a novel missence mutation (p.T907M) in five families, and a splice donor site mutation c.2986 + 2 T > G in the other family.</p> <p>Conclusion</p> <p>We have described two novel mutations in the gene <it>NPR2.</it> The presence of the same mutation (p.T907M) and haplotype in five families (A, B, C, D, E) is suggestive of a founder effect.</p

C-type natriuretic peptide and NPR-B signalling inhibits cardiac sympathetic neurotransmission and autonomic function.

AIMS: B-type natriuretic peptide (BNP)-NPR-A receptor signalling inhibits cardiac sympathetic neurotransmission, although, C-type natriuretic peptide (CNP) is the predominant neuropeptide of the nervous system with expression in the heart and vasculature. We hypothesised that CNP acts similarly to BNP, and that transgenic rats (TGR) with neuron specific overexpression of a dominant negative NPR-B receptor would develop heightened sympathetic drive. METHODS AND RESULTS: Mean arterial pressure (MAP) and heart rate (HR) were significantly (p&lt;0.05) elevated in freely moving TGRs (n=9) compared to Sprague Dawley (SD) controls (n=10). TGR had impaired left ventricular systolic function (LVSF) and spectral analysis of HR variability suggested a shift towards sympathoexcitation. Immunohistochemistry demonstrated co-staining of NPR-B with tyrosine hydroxylase in stellate ganglia neurons. In SD rats CNP (250nM, n=8) significantly reduced the tachycardia during right stellate ganglion stimulation (1-7Hz) in-vitro whilst the response to bath applied norepinephrine (NE, 1μM, n=6) remained intact. CNP (250nM, n=8) significantly reduced the release of (3)H-NE in isolated atria and this was prevented by the NPR-B antagonist P19 (250nM, n=6). The neuronal Ca(2+) current (n=6) and intracellular Ca(2+) transient (n=9, using fura-2AM) were also reduced by CNP in isolated stellate neurons. Treatment of the TGR (n=9) with the sympatholytic clonidine (125 µg/kg per day) significantly reduced MAP and HR to levels observed in the SD (n=9). CONCLUSIONS: CNP reduces cardiac sympathetic neurotransmission via a reduction in neuronal calcium signalling and NE release through the NPR-B receptor. Situations impairing CNP-NPR-B signalling lead to hypertension, tachycardia, and impaired LVSF secondary to sympatho-excitation