Regulation of polarized growth initiation and termination cycles by the polarisome and Cdc42 regulators

The dynamic regulation of polarized cell growth allows cells to form structures of defined size and shape. We have studied the regulation of polarized growth using mating yeast as a model. Haploid yeast cells treated with high concentration of pheromone form successive mating projections that initiate and terminate growth with regular periodicity. The mechanisms that control the frequency of growth initiation and termination under these conditions are not well understood. We found that the polarisome components Spa2, Pea2, and Bni1 and the Cdc42 regulators Cdc24 and Bem3 control the timing and frequency of projection formation. Loss of polarisome components and mutation of Cdc24 decrease the frequency of projection formation, while loss of Bem3 increases the frequency of projection formation. We found that polarisome components and the cell fusion proteins Fus1 and Fus2 are important for the termination of projection growth. Our results define the first molecular regulators that control the timing of growth initiation and termination during eukaryotic cell differentiation.     

A novel radioprotective function for the mitochondrial tumor suppressor protein Fus1

FUS1/TUSC2 is a mitochondrial tumor suppressor with activity to regulate cellular oxidative stress by maintaining balanced ROS production and mitochondrial homeostasis. Fus1 expression is inhibited by ROS, suggesting that individuals with a high level of ROS may have lower Fus1 in normal tissues and, thus, may be more prone to oxidative stress-induced side effects of cancer treatment, including radiotherapy. As the role of Fus1 in the modulation of cellular radiosensitivity is unknown, we set out to determine molecular mechanisms of Fus1 involvement in the IR response in normal tissues. Mouse whole-body irradiation methodology was employed to determine the role for Fus1 in the radiation response and explore underlying molecular mechanisms. Fus1^−/− mice were more susceptible to radiation compared with Fus1^+/+ mice, exhibiting increased mortality and accelerated apoptosis of the GI crypt epithelial cells. Following untimely reentrance into the cell cycle, the Fus1^−/− GI crypt cells died at accelerated rate via mitotic catastrophe that resulted in diminished and/or delayed crypt regeneration after irradiation. At the molecular level, dysregulated dynamics of activation of main IR response proteins (p53, NFκB, and GSK-3β), as well as key signaling pathways involved in oxidative stress response (SOD2, PRDX1, and cytochrome c), apoptosis (BAX and PARP1), cell cycle (Cyclins B1 and D1), and DNA repair (γH2AX) were found in Fus1^−/− cells after irradiation. Increased radiosensitivity of other tissues, such as immune cells and hair follicles was also detected in Fus1^−/− mice. Our findings demonstrate a previously unknown radioprotective function of the mitochondrial tumor suppressor Fus1 in normal tissues and suggest new individualized therapeutic approaches based on Fus1 expression.     

A novel link between a rab GTPase and Rvs proteins: the yeast amphiphysin homologues

The BAR proteins are a well-conserved family of proteins including Rvsp in yeast, amphiphysins and Bin proteins in mammals. In yeast, as in mammals, BAR proteins are known to be implicated in vesicular traffic. The Gyp5p (Ypl249p) and Ymr192p proteins interact in two-hybrid tests with both Rvs161p and Rvs167p. Gyp5p is a Ypt/Rab-specific GAP and Ymr192p is highly similar to Gyp5p. To specify the interaction between Rvsp and Gyp5p, we used two-hybrid tests to determine the domains necessary for these interactions. The specific SH3 domain of Rvs167p interacted with the N-terminal domain of Gyp5p. Moreover, Gyp5p could form a homodimer. Fus2 protein is a specific partner of Rvs161p in two-hybrid tests. To characterize the functional relationships between these five proteins, we have studied cellular phenotypes in single, double and triple mutant strains for which rvs mutants present defects, such as polarity, cell fusion and meiosis. Phenotypic analysis showed that Gyp5p, Ymr192p and Fus2p were involved in bipolar budding pattern and in meiosis. Specific epistasis or suppressive phenomena were found between the five mutations. Finally, The Gyp5p-GFP fusion protein was localized at the bud tip during apical growth and at the mother-bud neck during cytokinesis. Moreover, Rvs167p and Rvs161p were shown to be essential for the correct localization of Gyp5p. Altogether, these data support the hypothesis that both Rvsp proteins act in vesicular traffic through physical and functional interactions with Ypt/Rab regulators.     

Selective regulation of MAP kinase signaling by an endomembrane phosphatidylinositol 4-kinase

Multiple MAP kinase pathways share components yet initiate distinct biological processes. Signaling fidelity can be maintained by scaffold proteins and restriction of signaling complexes to discreet subcellular locations. For example, the yeast MAP kinase scaffold Ste5 binds to phospholipids produced at the plasma membrane and promotes selective MAP kinase activation. Here we show that Pik1, a phosphatidylinositol 4-kinase that localizes primarily to the Golgi, also regulates MAP kinase specificity but does so independently of Ste5. Pik1 is required for full activation of the MAP kinases Fus3 and Hog1 and represses activation of Kss1. Further, we show by genetic epistasis analysis that Pik1 likely regulates Ste11 and Ste50, components shared by all three MAP kinase pathways, through their interaction with the scaffold protein Opy2. These findings reveal a new regulator of signaling specificity functioning at endomembranes rather than at the plasma membrane.     

我国蝮属蛇类和尖吻蝮英文名称的建议

“Vipers“ is the English common name for more than 200 species of the family Viperidae. The so called “pit vipers“ is also the English common name for more than 150 species of the subfamily Crotalinae which have a “faclal pit“, an organ on each side of head which functions as a heat receptor. Of course, in countries where the people use English as the mother language there are English names for most snakes found in their own country. For example, the pit-viper species Agkistrodon contortrix is called “copperhead“, and Agkistrodon piscivorus is called “cottonmouth“ or “water moccasin“ in the USA. Also, another pit-viper, Agkistrodon bilineatus, is called “cantil“ by the people in Mexico and South America. In Japan, there has only one species belonging to the genus Glo3dius, i.e., Gloydius blornhoffii. According to its Japanese pronunciation, it has an English name by spelling of English alphabets as “mamushi“. Up to date, there are more than ten species recognized in the genus Gloydius. Among them , most are found in China. But there is no English common name especially for those species. After my detail studying, I certainly believe that there a Chinese word, “腹“ (according to Chinese pronunciation, it may be spelled by English alphabets as “Fu“) especially for the pit-viper species since 500 to 300 years B.C. During the following 2500 years, the snake name “Fu“ appeared in many ancient Chinese boaks dealing about dictionary (the “Ya“ course), drug boaks (Ben Cao), and even literature boaks or papers. So, the author of this paper used “腹“ as Chinese name for all the Gloydius species as well as for Deinagkistrodon acutus, because the latter was never included in the same genus. In this paper the author would suggest to use the English alphabet spelling “Fu“ plus “s“ (Fus) as an English name for the genus Gloydius, and “Fu “ as the English name of all the Gloydius species found in China and other places (excluding Gloydius blomhoffii found only in Japan, which still would keep its Japanese name “mamushi“). Besides, using “Sharp-snouted Fu“ as an English name of the genus Deinagkistrodon as well as species name of Deinagkistrodon acutus.