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PubMed2002

Microanatomical localization of PD-1 in human tonsils.

PD-1 is an immunoinhibitory receptor, which belongs structurally to the CD28 family. PD-1-deficient mice show breakdown of peripheral tolerance and manifest multiple autoimmune symptoms. We previously described expression of PD-1 on activated T and B lymphocytes and myeloid cells. However, little is known about the microanatomical distribution of PD-1 in lymphoid organs. In this study, we performed immunohistochemistry using monoclonal antibodies against human PD-1. In human tonsils, PD-1 was expressed on most of T cells and a small subset of centrocytes in the light zone of germinal centers (GCs), where clonal selection of centrocytes takes place. These results suggest that PD-1 may play an important role in GC reaction.

Adolescent↗
PubMed2002

Impairment of pronation, supination, and body co-ordination in reach-to-grasp tasks in human Parkinson's disease (PD) reveals homology to deficits in animal models.

Animal (monkey, rat, mouse) models are widely used to investigate degenerative processes and potential therapeutic treatments for human Parkinson's disease (PD). One task that has proved useful in these investigations is a reach-to-grasp task (skilled reaching) in which an animal reaches for a piece of food that it then consumes. Rats with extensive unilateral Dopamine depletions are impaired in using the contralateral limb. The qualitative features of posture, lifting and advancing the limb, pronating the paw to grasp food, and in withdrawing and supinating the paw to place the food in the mouth are impaired, as is reaching success. Humans with PD are often described as having poor manual dexterity that worsens as the disease progresses. As there have been no detailed comparisons of reaching movements in the animal models and in PD subjects, the following descriptive analysis was performed. Ten subjects with PD, eight age matched controls and 14 young normal subjects were studied as they used a natural movement of reaching for a small piece of food that they then placed in the mouth to eat. The reaching movements were described using Eshkol-Wachman Movement Notation (EWMN), supplemented with kinematic analyses. From this description, a 21-point rating scale was devised to describe the component movements of the reach. Movements included: orienting the head and eyes to the target, adjusting posture, lifting the hand, shaping and aiming the digits to the target, pronating the hand to grasping the food with a pincer grip, lifting and supinating the hand to transporting the food to the mouth, and further supinating the hand and opening the digits to place food in the mouth, and finally returning the hand to the starting position. Analysis indicated that most aspects of the reaching movements of the PD subjects were significantly different relative to both young control subjects and old control subjects. As compared to the control groups, postural and reaching components of the movements were fragmented, movements were achieved using more proximal segments of the body, and rotatory movements of the hand were limited. The PD subjects did use a pincer grasp to obtain the food, but the grasp was less independent of other digit movements than was observed in the control subjects. These results are discussed in terms of a homology to impairments displayed animal models of PD.

Adult↗
PubMed1998

The MEK inhibitor PD 098059 inhibits prolactin-induced Nb2 cell mitogenesis but not milk product synthesis in cultured mouse mammary tissues.

The MAP kinase pathway has been shown to be active in many growth factor signaling systems, including that of prolactin (PRL). In our studies, the main objective was to examine the possible involvement of MEK kinases (Map/Erk kinase kinases) in PRL-stimulated mitogenic and lactogenic processes. We used the MEK kinase inhibitor PD 098059 to block MEK kinase activation in the Nb2 cell line and mammary gland explants derived from 12- to 14-day pregnancy mice. PD 098059 attenuated PRL-induced Nb2 cell mitogenesis at 10 microM and a maximum inhibition was observed at 100 microM. In cultured mammary tissues, PD 098059 at 100 microM had no effect on the PRL stimulation of lipid, casein and lactose synthesis and iodide uptake. Further, the growth-inhibitory effect of PD 098059 on Nb2 cells was ameliorated when the drug was removed from the culture medium, indicating that PD 098059 acts in a reversible manner. When MEK1 was immunoprecipitated from PD 098059 and/or PRL treated Nb2 cells, PRL-stimulated MEK1 kinase activity was directly inhibited by PD 098059 at concentrations employed in the culture experiments. PRL has no effect on the tyrosyl phosphorylation of MAP kinases in cultured mammary tissues derived from pregnant mice, whereas earlier we found that PRL stimulates the tyrosyl phosphorylation of all four MAP kinases in Nb2 cells. The results suggest that the MAP kinase pathway plays an important role in the PRL stimulation of Nb2 cell mitogenesis but is not involved in the PRL stimulation of milk product synthesis.

Animals↗
PubMed2003

Pd-ECGF positivity correlates with better survival, while iNOS has no predictive value for cervical carcinomas treated with radiotherapy.

PURPOSE: Platelet-derived endothelial cell growth factor (PD-ECGF), which has angiogenic activity, is identical to thymidine phosphorylase. Tumor vascularization is considered to be an important prognostic factor. Nitric oxide synthases (NOSs) are a kind of enzyme that generates nitric oxide. Nitric oxide has not only a self defense against neoplastic cells but also tumor growth stimulation by promoting new blood vessel formation. Our purpose was to investigate the correlation between the expression of PD-ECGF or inducible NOS (iNOS) in cancer cells and prognosis. METHODS AND MATERIALS: Formaldehyde-fixed and paraffin-embedded biopsy specimens excised from 71 cervical squamous cell carcinoma patients who were treated with radiotherapy alone were investigated using an immunohistochemical method. RESULTS: Cancer cells that were positive for PD-ECGF showed intranuclear and cytoplasmic staining patterns. Of the 71 patients, 40 (56%) were positive for PD-ECGF and 31 (44%) were negative. The 5-year survival of the PD-ECGF-positive patients was significantly better than that of the PD-ECGF-negative patients (p = 0.026). Cancer cells that were positive for iNOS showed a cytoplasmic staining pattern. Twenty-seven patients (38%) were positive for iNOS and 44 (62%) were negative. No significant prognostic correlation was observed between iNOS-positive and iNOS-negative patients. CONCLUSION: PD-ECGF positivity in cancer cells is a predictive factor for a good prognosis in cervical squamous cell carcinoma treated with radiotherapy alone.

Adult↗
PubMed2002

Animal models of PD: pieces of the same puzzle?

Parkinson's disease (PD) is a common neurodegenerative disorder with no known cure. The etiology of PD is likely due, in part, to combinations of genetic susceptibilities and environmental factors. In rare familial cases, PD is due to genetic mutations. A number of new genetic and toxin models of PD and advances in older models are yielding important new information about the pathogenesis of PD. This has prompted us to critically review the current animal models for PD and discuss how these models may yield fresh insights into the pathogenesis of PD, as well as new therapeutic opportunities.

Animals↗
PubMed2001

PD-1: an inhibitory immunoreceptor involved in peripheral tolerance.

PD-1 deficiency causes a variety of autoimmune diseases. Inhibitory signaling through the PD-1 receptor might therefore be involved in the regulation of peripheral tolerance. The constitutive expression of PD-1 ligands (PD-L1 and PD-L2) on parenchymal cells of heart, lung and kidney suggests that the PD-1-PD-L system could provide unique negative signaling to help prevent autoimmune diseases.

Animals↗
PubMed2002

Polyatomic clusters of the triel elements. Palladium-centered clusters of thallium in A(8)Tl(11)Pd, A = Cs, Rb, K.

Reactions of the elements within welded Ta containers at approximately 600 degrees C followed by slow cooling give new A(8)Tl(11)Pd(x) products from an apparently continuous encapsulation of Pd atoms into the pentacapped trigonal prismatic anions in the isotypic rhombohedral (R3 macro c) A(8)Tl(11) phases. All systems also produce other phases at x < 1 as well, the simplest being the cesium system in which only trigonal Pd(13)Tl(9) is also formed. Cs(8)Tl(11)Pd(0.84(1)) was characterized by single-crystal means as close to the upper x limit in that system (R3 macro c, Z = 6, a = 10.610(1) A, c = 54.683(8) A). The Pd insertion causes an expansion of the D(3) host anion, particularly about the waist, to generate a trigonal bipyramidal PdTl(5) unit (d(Pd-Tl) approximately 2.6-2.8 A) centered within a somewhat larger Tl(6) trigonal prism, the remainder of the Tl(11) cluster. Strong Tl cage bonding is retained. Extended Hückel calculations show significant involvement of all Tl 6s, 6p and Pd 4d, 5s, 5p orbital sets in the central and cage bonding. The last valence electron is considered to be delocalized in a conduction band, as in A(8)Tr(11) examples, rather than occupying an antibonding e'' LUMO across a gap of approximately 2.4 eV.

Journal Article↗
PubMed2006

Reactivity of (ferrocenylmethyl)phosphine toward palladium and platinum chlorides. X-ray structure of [Pd(PH2CH2Fc)Cl(mu-PHCH2Fc)]4 (Fc = ferrocenyl), a unique complex containing a Pd4P4 cycle.

The reaction of 2 equiv of the air-stable primary phosphine (ferrocenylmethyl)phosphine (PH2CH2Fc, 1) with [Pd(cod)Cl2] (Fc = ferrocenyl; cod = 1,5-cyclooctadiene) at 298 K gave the phosphanido-bridged Pd(II) tetramer [Pd(PH2CH2Fc)Cl(mu-PHCH2Fc)]4 (2), which shows an unprecedented arrangement of four Pd atoms embedded in an eight-membered Pd4P4 ring. An X-ray diffraction study showed that 2 crystallizes in the triclinic space group P with a = 17.607(7) A, b = 17.944(7) A, c = 18.792(7) A, alpha = 107.120(12) degrees, beta = 96.344(13) degrees, gamma = 117.087(15) degrees . Each molecule contains four palladium atoms in a distorted square-planar coordination formed by one chlorine and three phosphorus atoms. Two of the latter belong to bridging primary phosphanides and the remaining one is contributed by a terminal PH2CH2Fc ligand. The coordination environments of neighboring metal centers adopt an almost perpendicular mutual orientation. The reaction of 2 equiv of 1 with [Pt(cod)Cl2] at 323 K yielded the analogous Pt(II) tetramer of formula [Pt(PH2CH2Fc)Cl(mu-PHCH2Fc)]4 (3), which was fully characterized by multinuclear and dynamic NMR, IR, and elemental analyses. Single-crystal X-ray diffraction on 3 confirmed the tetranuclear arrangement in the solid state, but orientational disorder of the molecule precludes a more detailed discussion of the structure. Low-temperature NMR experiments in CD2Cl2 showed the presence of two slowly interconnecting conformers. Reaction of 1 and [M(cod)Cl2] (M = Pd or Pt) at lower temperatures (273 K for Pd, 295 K for Pt) in dichloromethane allowed the detection in solution of the mononuclear species cis-[M(PH2CH2Fc)2Cl2] (M = Pd, 4; M = Pt, 5) which, upon heating, transformed into the tetramers 2 and 3, respectively. Solid samples of 4 and 5 could be isolated after workup at low temperature and were characterized by conventional spectroscopic methods.

Journal Article↗
PubMed2004

Synthetic, structural, and mechanistic aspects of an amine activation process mediated at a zwitterionic Pd(II) center.

A zwitterionic palladium complex [[Ph(2)BP(2)]Pd(THF)(2)][OTf] (1) (where [Ph(2)BP(2)] = [Ph(2)B(CH(2)PPh(2))(2)](-)) reacts with trialkylamines to activate a C-H bond adjacent to the amine N atom, thereby producing iminium adduct complexes [Ph(2)BP(2)]Pd(N,C:eta(2)-NR(2)CHR'). In all cases examined the amine activation process is selective for the secondary C-H bond position adjacent to the N atom. These palladacycles undergo facile beta-hydride elimination/olefin reinsertion processes as evident from deuterium scrambling studies and chemical trap studies. The kinetics of the amine activation process was explored, and beta-hydride elimination appears to be the rate-limiting step. A large kinetic deuterium isotope effect for the amine activation process is evident. The reaction profile in less polar solvents such as benzene and toluene is different at room temperature and leads to dimeric [[Ph(2)BP(2)]Pd](2) (4) as the dominant palladium product. Low-temperature toluene-d(8) experiments proceed more cleanly, and intermediates assigned as [Ph(2)BP(2)]Pd(NEt(3))(OTf) and the iminium hydride species [[Ph(2)BP(2)]Pd(H)(Et(2)N=CHCH(3))][OTf] are directly observed. The complex (Ph(2)SiP(2))Pd(OTf)(2) (14) was also studied for amine activation and generates dimeric [(Ph(2)SiP(2))Pd](2)[OTf](2) (16) as the dominant palladium product. These collective data are discussed with respect to the mechanism of the amine activation and, in particular, the influence that solvent polarity and charge have on the overall reaction profile.

Journal Article↗
PubMed2006

Zn adsorption on Pd(111): ZnO and PdZn alloy formation.

The adsorption and thermal desorption of Zn and ZnO on Pd(111) was studied in the temperature range between 300 and 1300 K with TDS, LEED, and CO adsorption measurements. At temperatures below 400 K, multilayer growth of Zn metal on the Pd(111) surface takes place. At a coverage of 0.75 ML of Zn, a p(2 x 2)-3Zn LEED structure is observed. Increasing the coverage to 3 ML results in a (1 x 1) LEED pattern arising from an ordered Zn multilayer on Pd(111). Thermal desorption of the Zn multilayer state leads to two distinct Zn desorption peaks: a low-temperature desorption peak (400-650 K) arising from upper Zn layers and a second peak (800-1300 K) originating from the residual 1 ML Zn overlayer, which is more strongly bound to the Pd(111) surface and blocks CO adsorption completely. Above 650 K, this Zn adlayer diffuses into the subsurface region and the surface is depleted in Zn, as can be deduced from an increased amount of CO adsorption sites. Deposition of >3 ML of Zn at 750 K leads to the formation of a well-ordered Pd-Zn alloy exhibiting a (6 x 4 square root 3/3)rect. LEED structure. CO adsorption measurements on this surface alloy indicate a high Pd surface concentration and a strong reduction of the CO adsorption energy. Deposition of Zn at T > 373 K in 10(-6) mbar of O2 leads to the formation of an epitaxial (6 x 6) ZnO overlayer on Pd(111). Dissociative desorption of ZnO from this overlayer occurs quantitatively both with respect to Zn and O2 above 750 K, providing a reliable calibration for both ZnO, Zn, and oxygen coverage.

Journal Article↗
PubMed2006

Interactions of hydrogen with Pd and Pd/Ni alloy chain-functionalized single walled carbon nanotubes from density functional theory.

Density functional theory is employed to study Pd and Pd/Ni alloy monatomic chain-functionalized metallic single walled carbon nanotubes (SWNT(6,6)) and semiconducting SWNT(10,0), and their interactions with hydrogen molecules. The stable geometries and binding energies have been determined for both isolated chains and chains on SWNT surfaces. We found that continuous Pd and Pd/Ni chains form on SWNTs with geometries close to stable geometries in the isolated chains. Ni alloying improves stability of the chains owing to a higher binding energy to both Pd and C atoms. The physical properties of SWNTs are significantly modified by chain functionalization. SWNT(10,0) is transformed to metal by either Pd or alloy chains, or to a smaller band gap semiconductor, depending on the Pd binding site. From calculations for H(2) interactions with the optimized chain-SWNT systems, the adsorption energy per H atom is found to be about 2.6 times larger for Pd/Ni chain-functionalized SWNTs than for pure Pd chain-functionalized SWNTs. Band structure calculations show that the SWNT(10,0) reverts back to semiconductor and SWNT(6,6) has reduced density of states at the Fermi level upon H(2) adsorption. This result is consistent with the experimentally observed increase of electrical resistance when Pd-coated SWNTs are used as H(2) sensing materials. Finally, our results suggest that Pd/Ni-SWNT materials are potentially good H(2)-sensing materials.

Journal Article↗
PubMed1999

Expression of platelet-derived endothelial cell growth factor (PD-ECGF) and its mRNA in uterine cervical cancers.

Angiogenesis contributes to the growth and secondary spreading of solid tumours. Platelet-derived endothelial cell growth factor (PD-ECGF) is identified as such an angiogenic factor. In the present study, the prognosis of the patients with high PD-ECGF uterine cervical cancers was worse than those with low PD-ECGF cancers, and PD-ECGF expression correlated with cellular proliferation and with vascular density and venous invasion in uterine cervical cancers. Therefore, PD-ECGF might contribute to the growth of uterine cervical cancers via angiogenesis related to vascular spreading. Furthermore, PD-ECGF and its mRNA had a wide range and were highly expressed in uterine cervical cancers, especially squamous cell carcinoma, regardless of clinical stage. Therefore, PD-ECGF in uterine cervical cancers might play a role of basic angiogenesis in all processes of advancing of uterine cervical cancers. This indicates that 5'-deoxy-5-fluorouridine might be highly effective in squamous cell carcinoma of the cervix, which possesses a high activity of thymidine phosphorylase to convert 5'-deoxy-5-fluorouridine to 5-fluorouracil, and that some angiogenic inhibitors of new capillary formation might be effective in the inhibition of tumour growth and spreading associated with angiogenesis.

Adult↗
PubMed1999

PD 098059, an inhibitor of ERK1 activation, attenuates the in vivo invasiveness of head and neck squamous cell carcinoma.

Increased mortality of patients with oral cancer largely reflects the local and regional spread of the disease. The invasiveness of these tumours requires hydrolases which are regulated through AP-1-dependent transcriptional mechanisms. Since the amount/activity of transcription factors bound to the AP-1 motif are regulated partly through the extracellular signal-regulated kinases (ERK1/ERK2), we determined the effect of PD 098059, an inhibitor of ERK1/ERK2 activation, on the in vivo invasiveness of a human squamous cell carcinoma cell line (UM-SCC-1) derived from the oral cavity. We utilized the floor of mouth musculature consisting of the mylohyoid, geniohyoid and genioglossus muscle (which are sequentially arranged), as a natural barrier to assess tumour spread in vivo in the nude mouse. Mice were inoculated with tumour cells superficial to the mylohyoid muscle. After 18 days, tumours were injected with either empty liposomes (control) or liposomes containing 5 microM PD 098059 and, after an additional 22 days, the jaws of mice examined histologically. Highly infiltrative tumours, which had penetrated the genioglossus muscle, were evident in 10/12 control mice. In contrast, in 9/12 mice in which the tumours were injected with PD 098059, tumours did not extend beyond the mylohyoid or geniohyoid muscles. Tumours penetrated bone nutrient canals in 7/12 control mice but in only 3/12 PD 098059-treated mice. Neurotropism, characteristic of aggressive oral squamous cell carcinoma, was evident in 6/12 control mice but was completely abolished (0/12 mice) in the PD 098059-treated mice. Using a staging system based on the muscle layer involved, neurotropism, as well as bone involvement, we found the inhibition of invasion to be statistically significant (P < 0.01). The reduced invasiveness of the PD 098059-liposome-treated oral cancers was associated with diminished 92-kDa type IV collagenase and ERK1/ERK2 activities but was not a consequence of a slower tumour growth rate. This is the first study to demonstrate reduced in vivo invasiveness of a malignancy brought about by an inhibitor of ERK1/ERK2 activation. These results raise the exciting possibility that second generation PD 098059 congeners may reduce the spread of the disease in patients afflicted with oral cancers.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2004

Insertion reactions of SO2 into Pd-OR bonds: preparation of alkyl sulfito complexes of palladium(II).

Mononuclear palladium-hydroxo complexes of the type [Pd(N-N)(C6F5)(OH)][(N-N = 2,2'-bipyridine (bipy), 4,4'-dimethyl-2,2'-bipyridine (Me2bipy), or N,N,N',N'-tetramethylethylenediamine (tmeda) react with SO2(1 atm) at room temperature in alcohol (methanol, ethanol, propanol or isopropanol) to yield alkyl sulfito palladium complexes [Pd(N-N)(C6F5)(SO2OR)](R = Me, Et, Pr or iPr). Similar alkyl sulfito complexes [Pd(N-N)(C6F5)(SO2OR)](N-N = bis(3,5-dimethylpyrazol-1-yl)methane); R = Me or Et) are obtained when [Pd(N-N)(C6F5)Cl] is treated with KOH in the corresponding alcohol ROH and SO2 is bubbled through the solution. The reaction of [Pd(bipy)(C6F5)(OH)] with SO2 in tetrahydrofuran gives [Pd(N-N)(C6F5)(SO2OH)]. The X-ray diffraction study of [Pd(tmeda)(C6F5)(SO2OPr)] has established the sulfur coordination of the propyl sulfito ligand.

Journal Article↗
PubMed2005

First-principles study of some factors controlling the rate of ammonia decomposition on Ni and Pd surfaces.

Using the plane-wave pseudopotential method within the density-functional theory with the generalized gradient approximation for exchange and correlation potential, we have calculated adsorption energies (E(ad)), diffusion barrier, and the first dissociation barrier (E(1)) for NH(3) on Ni and Pd surfaces. While the top site is found to be preferred for NH(3) adsorption on both Ni(111) and Pd(111), its calculated diffusion barrier is substantially higher for Pd(111) than for Ni(111). We also find that during the first dissociation step (NH(3)-->NH(2)+H), NH(2) moves from the top site to the nearest hollow site on Ni(111) and Pd(111) and on the stepped surfaces, Ni(211) and Pd(211), it moves from the initial top site at the step edge to the bridge site in the same atomic chain. Meanwhile H is found to occupy the hollow sites on all four surfaces. On Ni(111), E(1) is found to be 0.23 eV higher than E(ad), while at the step of Ni(211), E(1) and E(ad) are almost equal, suggesting that the probability for the molecule to dissociate is much on the step of Ni(211). In the case of Pd(211), however, we find that the dissociation barrier is much higher than E(ad). These trends are in qualitative agreement with the experimental finding that ammonia decomposition rate is much lower on Pd than on Ni.

Journal Article↗
PubMed2006

Theoretical prediction of noble-gas compounds: Ng-Pd-Ng and Ng-Pt-Ng.

Following our recent study on Ng-Pt-Ng (Ng=Ar,Kr,Xe) [J. Chem. Phys. 123, 204321 (2005)], the binding of noble-gas atoms with Pd atom has been investigated by the ab initio coupled cluster CCSD(T) method with counterpoise corrections, including relativistic effects. It is shown that two Ng atoms bind with Pd atom in linear geometry due to the s-d(sigma) hybridization in Pd where the second Ng atom attaches with much larger binding energy than the first. The binding energies are evaluated as 4.0, 10.2, and 21.5 kcalmol for Ar-Pd-Ar, Kr-Pd-Kr, and Xe-Pd-Xe, respectively, relative to the dissociation limit, Pd ((1)S)+2Ng. In the hybrid Ng complexes, the binding energies for XePd and Ng (=Ar,Kr) are evaluated as 4.0 and 6.9 kcalmol for XePd-Ar and XePd-Kr, respectively. The fundamental frequencies and low-lying vibrational-rotational energy levels are determined for each compound by the variational method, based on the three-dimensional near-equilibrium potential energy surface. Results of vibrational-rotational analyses for Ng-Pt-Ng (Ng=Ar,Kr,Xe) and Xe-Pt-Ng (Ng=He,Ne,Ar,Kr) compounds are also given.

Journal Article↗
PubMed1995

PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo.

PD 098059 has been shown previously to inhibit the dephosphorylated form of mitogen-activated protein kinase kinase-1 (MAPKK1) and a mutant MAPKK1(S217E,S221E), which has low levels of constitutive activity (Dudley, D. T., Pang, L., Decker, S. J., Bridges, A. J., and Saltiel, A. R. (1995) Proc. Natl. Acad. Sci. U.S.A. 92, 7686-7689). Here we report that PD 098059 does not inhibit Raf-activated MAPKK1 but that it prevents the activation of MAPKK1 by Raf or MEK kinase in vitro at concentrations (IC50 = 2-7 microM) similar to those concentrations that inhibit dephosphorylated MAPKK1 or MAPKK1(S217E,S221E). PD 098059 inhibited the activation of MAPKK2 by Raf with a much higher IC50 value (50 microM) and did not inhibit the phosphorylation of other Raf or MEK kinase substrates, indicating that it exerts its effect by binding to the inactive form of MAPKK1. PD 098059 also acts as a specific inhibitor of the activation of MAPKK in Swiss 3T3 cells, suppressing by 80-90% its activation by a variety of agonists. The high degree of specificity of PD 098059 in vitro and in vivo is indicated by its failure to inhibit 18 protein Ser/Thr kinases (including two other MAPKK homologues) in vitro by its failure to inhibit the in vivo activation of MAPKK and MAP kinase homologues that participate in stress and interleukin-1-stimulated kinase cascades in KB and PC12 cells, and by lack of inhibition of the activation of p70 S6 kinase by insulin or epidermal growth factor in Swiss 3T3 cells. PD 098059 (50 microM) inhibited the activation of p42MAPK and isoforms of MAP kinase-activated protein kinase-1 in Swiss 3T3 cells, but the extent of inhibition depended on how potently c-Raf and MAPKK were activated by any particular agonist and demonstrated the enormous amplification potential of this kinase cascade. PD 098059 not only failed to inhibit the activation of Raf by platelet-derived growth factor, serum, insulin, and phorbol esters in Swiss 3T3 cells but actually enhanced Raf activity. The rate of activation of Raf by platelet-derived growth factor was increased 3-fold, and the subsequent inactivation that occurred after 10 min was prevented. These results indicate that the activation of Raf is suppressed and that its inactivation is accelerated by a downstream component(s) of the MAP kinase pathway.

Amino Acid Sequence↗
PubMed2005

PD-1/PD-L pathway and autoimmunity.

Programmed cell death 1 (PD-1) was isolated in 1992 by subtractive-hybridization technique, as a molecule whose expression is enhanced by apoptotic stimuli. Since then we have been analyzing the function of PD-1 in the regulation of immune responses. Generation of PD-1 deficient mice, pathophysiological analyses of autoimmune diseases in PD-1 deficient mice, identification of two ligands, and analyses of downstream events of PD-1 revealed that PD-1 prevents autoimmunity by inhibiting activation of self-reactive lymphocytes. These findings were further applied on human autoimmune diseases and single nucleotide polymorphisms (SNPs) on human PD-1 gene have been reported to link with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and type I diabetes.

Animals↗