"Prediction in Multivariate Mixed Linear Models"

The multivariate mixed linear model or multivariate components of variance model with equal replications is considered.The paper addresses the problem of predicting the sum of the regression mean and the random e ects.When the feasible best linear unbiased predictors or empirical Bayes predictors are used,this prediction problem reduces to the estimation of the ratio of two covariance matrices.We propose scale invariant Stein type shrinkage estimators for the ratio of the two covariance matrices.Their dominance properties over the usual estimators including the unbiased one are established, and further domination results are shown by using information of order restriction between the two covariance matrices.It is also demonstrated that the empirical Bayes predictors that employs these improved estimators of the ratio of the two covariance matrices have uniformly smaller risks than the crude Efron-Morris type estimator in the context of estimation of a matrix mean in a xed e ects linear regression model where the components are unknown parameters.

Aur-A Stabilization in Cancer

Background. The serine/threonine kinase Aurora-A (Aur-A) is a proto-oncoprotein overexpressed in a wide range of human cancers. Overexpression of Aur-A is thought to be caused by gene amplification or mRNA overexpression. However, recent evidence revealed that the discrepancies between amplification of Aur-A and overexpression rates of Aur-A mRNA were observed in breast cancer, gastric cancer, hepatocellular carcinoma, and ovarian cancer. We found that aggressive head and neck cancers exhibited overexpression and stabilization of Aur-A protein without gene amplification or mRNA overexpression. Here we tested the hypothesis that aberration of the protein destruction system induces accumulation and consequently overexpression of Aur-A in cancer. Principal Findings. Aur-A protein was ubiquitinylated by APCCdh1 and consequently degraded when cells exited mitosis, and phosphorylation of Aur-A on Ser51 was observed during mitosis. Phosphorylation of Aur-A on Ser51 inhibited its APCCdh1-mediated ubiquitylation and consequent degradation. Interestingly, constitutive phosphorylation on Ser51 was observed in head and neck cancer cells with protein overexpression and stabilization. Indeed, phosphorylation on Ser51 was observed in head and neck cancer tissues with Aur-A protein overexpression. Moreover, an Aur-A Ser51 phospho-mimetic mutant displayed stabilization of protein during cell cycle progression and enhanced ability to cell transformation. Conclusions/Significance. Broadly, this study identifies a new mode of Aur-A overexpression in cancer through phosphorylation-dependent inhibition of its proteolysis in addition to gene amplification and mRNA overexpression. We suggest that the inhibition of Aur-A phosphorylation can represent a novel way to decrease Aur-A levels in cancer therapy

哺乳類の細胞周期進行モニターにおける制御異常と発がん感受性

金沢大学がん研究所1.G0/G1細胞周期の進行に重要な役割を担っている機能分子群のひとつ、4型サイクリン依存的キナーゼ(Cdk4)の恒常的活性型変異体(constitutively active form)遺伝子を哺乳類細胞に強制発現することによって、紫外線ならびにX線誘発G1進行阻害効果が起こらないことを見い出した。G1阻害のかからなくなった細胞株では、紫外線誘発染色分体異常の頻度が上昇した。また、X線誘発の染色分体ならびに染色体異常の頻度についても、コントロールの細胞群と比較して、高いことがわかった。2.細胞周期進行のチェックポイントを制御する機構を構成するような新たな因子を検索した。その結果、酵母のチェックポイント欠損変異株、chkの表現形質を相補する哺乳類細胞の遺伝子として、新たな候補遺伝子を単離した。この遺伝子は酵母の分裂異常多発変異株、iplを相補する酵母遺伝子iplと相同性を認めた。研究課題/領域番号:07272237, 研究期間(年度):1995出典：研究課題「哺乳類の細胞周期進行モニターにおける制御異常と発がん感受性」課題番号07272237（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07272237/）を加工して作

Landau-Ginzburg method applied to finite fermion systems: Pairing in Nuclei

Given the spectrum of a Hamiltonian, a methodology is developed which employs the Landau-Ginsburg method for characterizing phase transitions in infinite systems to identify phase transition remnants in finite fermion systems. As a first application of our appproach we discuss pairing in finite nuclei.Comment: 14 pages, 4 figure

PARP6 acts as a tumor suppressor via downregulating Survivin expression in colorectal cancer

Poly (ADP-ribose) polymerases (PARPs) are enzymes that transfer ADP-ribose groups to target proteins and are involved in a variety of biological processes. PARP6 is a novel member, and our previous findings suggest that PARP6 may act as a tumor suppressor via suppressing cell cycle progression. However, it is still unclear that PARP6 function besides growth suppression in colorectal cancer (CRC). In this study, we examined tumor suppressive roles of PAPR6 in CRC cells both in vitro and in vivo. We found that PARP6 inhibited colony formation, invasion and migration as well as cell proliferation. Moreover, ectopic overexpression of PARP6 decreased Survivin expression, which acts as an oncogene and is involved in apoptosis and mitosis. We confirmed the inverse correlation between PARP6 and Survivin expression in CRC cases by immunohistochemistry. Importantly, CRC cases with downregulation of PARP6 and upregulation of Survivin showed poor prognosis. In summary, PARP6 acts as a tumor suppressor via downregulating Survivin expression in CRC. PARP6 can be a novel diagnostic and therapeutic target together with Survivin for CRC

Phosphorylation by Aurora B Converts MgcRacGAP to a RhoGAP during Cytokinesis

AbstractCell division is finely controlled by various molecules including small G proteins and kinases/phosphatases. Among these, Aurora B, RhoA, and the GAP MgcRacGAP have been implicated in cytokinesis, but their underlying mechanisms of action have remained unclear. Here, we show that MgcRacGAP colocalizes with Aurora B and RhoA, but not Rac1/Cdc42, at the midbody. We also report that Aurora B phosphorylates MgcRacGAP on serine residues and that this modification induces latent GAP activity toward RhoA in vitro. Expression of a kinase-defective mutant of Aurora B disrupts cytokinesis and inhibits phosphorylation of MgcRacGAP at Ser387, but not its localization to the midbody. Overexpression of a phosphorylation-deficient MgcRacGAP-S387A mutant, but not phosphorylation-mimic MgcRacGAP-S387D mutant, arrests cytokinesis at a late stage and induces polyploidy. Together, these findings indicate that during cytokinesis, MgcRacGAP, previously known as a GAP for Rac/Cdc42, is functionally converted to a RhoGAP through phosphorylation by Aurora B