The Luteinizing hormone receptor (LHR) belongs to the G protein-coupled receptor family, asdo the other glycoprotein hormone receptors for FSH, TSH, and CG. The LHR comprises twohalves of ~350 amino acids: an extracellular hormone binding exodomain and a seventransmembrane-spanning endodomain responsible for signal generation. Hormone binds to theexodomain with high affinity, and the resulting conformational changes in thehormone/exodomain complex modulate the endodomain to generate hormone signals. Hormonebinding to an LHR produces hormonal signals (cis-activation), but it is not known whether aliganded LHR could activate other unoccupied LHRs (trans-activation). The LHR activates bothadenylyl cyclase and phospholipase C??. This dissertation shows that trans-activation of the LHRleads to the activation of adenylyl cyclase to induce cAMP but not to the activation ofphospholipase C?? to induce the inositol phosphate signaling. Trans-activation offers amechanism of signal amplification at the receptor level and also provides a mechanism ofmultiple signal generation for a liganded LHR to cis-activate phospholipase C?? and transactivateadenylyl cyclase. Also coexpression of Gi2 with a constitutively activating LHR(Asp578Gly), the most common mutation of male-limited precocious puberty, shows that Gi2could completely inhibit cAMP induction by the LHR mutant. Experiments using the carboxylterminal region of G protein ?? subunits demonstrate that LHR has overlapping binding sites forG?? subunits Gs and Gi2.

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Peptidyl-prolyl isomerization is an important post-translational modification of protein because proline is the only amino acid that can stably exist as cis and trans, while other amino acids are in the trans conformation in protein backbones. This makes prolyl isomerization a unique mechanism for cells to control many cellular processes. Isomerization is a rate-limiting process that requires a peptidyl-prolyl cis/trans isomerase (PPIase) to overcome the energy barrier between cis and trans isomeric forms. Pin1, a key PPIase in the cell, recognizes a phosphorylated Ser/Thr-Pro motif to catalyze peptidyl-prolyl isomerization in proteins. The significance of the phosphorylation-dependent Pin1 activity was recently highlighted for isomerization of ATR (ataxia telangiectasia- and Rad3-related). ATR, a PIKK protein kinase, plays a crucial role in DNA damage responses (DDR) by phosphorylating hundreds of proteins. ATR can form cis or trans isomers in the cytoplasm depending on Pin1 which isomerizes cis-ATR to trans-ATR. Trans-ATR functions primarily in the nucleus. The cis-ATR, containing an exposed BH3 domain, is anti-apoptotic at mitochondria by binding to tBid, preventing activation of pro-apoptotic Bax. Given the roles of apoptosis in many human diseases, particularly cancer, we propose that cytoplasmic cis-ATR enables cells to evade apoptosis, thus addicting cancer cells to cis-ATR formation for survival. But in normal DDR, a predominance of trans-ATR in the nucleus coordinates with a minimal level of cytoplasmic cis-ATR to promote DNA repair while preventing cell death; however, cells can die when DNA repair fails. Therefore, a delicate balance/equilibrium of the levels of cis- and trans-ATR is required to ensure the cellular homeostasis. In this review, we make a case that this anti-apoptotic role of cis-ATR supports oncogenesis, while Pin1 that drives the formation of trans-ATR suppresses tumor growth. We offer a potential, novel target that can be specifically targeted in cancer cells, without killing normal cells, to significantly reduce the adverse effects usually seen in cancer treatment. We also raise important issues regarding the roles of phosphorylation-dependent Pin1 isomerization of ATR in diseases and propose areas of future studies that would shed more understanding on this important cellular mechanism.

We developed an approach to the β-thioenamide linkage contained in the S-(2-aminovinyl)cysteine (avCys) residue of thioviridamide.1,2 Kinetic and thermodynamic control of radical additions of thiols to ynamides were studied for the formation of β-thioenamide linkage. Thiyl radicals are electrophilic and ynamides are electron-rich alkynes. This complementary polarity of the radical and acceptor increases the likelihood of a successful radical addition reaction. Because little is known about these types of compounds (β-thioenamides), we were unsure what kinds of yields and stereoselectivities (cis vs. trans) to expect. The adduct stability is another issue to consider. Fortunately, under typical radical addition conditions, the two separable isomers (cis and trans) are formed in good yield. Selective formation of kinetic (cis) and thermodynamic (trans) isomers are controlled by reaction time and equivalents of thiol. We converted the kinetic isomer to the thermodynamic isomer to confirm that isomerization can occur under the reaction conditions. Alkyl and aryl thiols including cysteine-derived thiols with different ynamides were used in this process.

3 ABSTRACT Complexes [Rh(cycloolefin)(acac)] (cycloolefin = norborna-2,5-diene, cycloocta- 1,5-diene and cyclooctatetraene) were investigated as catalysts of polymerization of monosubstituted acetylenes into stereoregular cis-transoid polyacetylenes. All complexes were highly active in arylacetylenes polymerizations in both coordinating and non-coordinating solvents. Selection of solvent and cycloolefin ligand of the catalyst allowed the control over polymer MW. The onset of initiation in the [Rh(cycloolefin)(acac)]/monomer systems proceeded as the proton transfer from the monomer molecule to the acac ligand under the release of acetylacetone and coordination of -C≡CR ligand to Rh(cycloolefin) moiety. Cis-transoid poly(phenylacetylene) and poly[(2,4-difluorophenyl)acetylene]s with required initial MW were prepared with these catalysts and submitted to the long-term ageing in which the polymers were exposed to the atmosphere and diffuse daylight either dissolved in tetrahydrofuran or in the solid state. Tightly connected processes of cis-to-trans isomerization of the polymer main-chains double bonds and oxidative degradation were found to proceed during polymers ageing in the solution. Besides, the formation of corresponding cyclotrimers accompanied the polymers ageing. However, the cyclotrimers amount was...