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Molecular and genetic characterizati...

Firestein, Ron.

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Molecular and genetic characterization of the roles of the Sbf1 pseudo-phosphatase in growth control and development.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Molecular and genetic characterization of the roles of the Sbf1 pseudo-phosphatase in growth control and development./
作者:	Firestein, Ron.
面頁冊數:	142 p.
附註:	Adviser: Michael Cleary.
Contained By:	Dissertation Abstracts International63-04B.
標題:	Biology, Animal Physiology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3048525
ISBN:	0493628568

Molecular and genetic characterization of the roles of the Sbf1 pseudo-phosphatase in growth control and development.
Firestein, Ron.

Molecular and genetic characterization of the roles of the Sbf1 pseudo-phosphatase in growth control and development. - 142 p.

Adviser: Michael Cleary.

Thesis (Ph.D.)--Stanford University, 2002.

The myotubularin family consists of a highly conserved group of proteins that have been linked to heritable human diseases and characterized as phosphoinositide phosphatases. Sbf1, originally identified by virtue of its interaction with SET domain/histone methyltransferase proteins, is a member of the myotubularin family. It is unique however in that it lacks phosphatase activity due to evolutionarily conserved amino acid changes in its catalytic pocket. Herein, we characterize the properties of Sbf1. Structural analyses of wildtype reveal that it is a cytoplasmic protein, however N-terminal mutations partially localize Sbf1 to the nucleus and lead to oncogenic transformation in tissue culture. In addition, oncogenically active forms of Sbf1 are capable of interacting with and modulating the function of SUV39H1, a SET domain protein that possesses histone methyltransferase activity. Sbf1 perturbs the transcriptional repression, cell growth inhibition and nuclear localization of SUV39H1 in a phosphorylation-dependent manner. Sbf1 is highly expressed in both Sertoli cells and spermatogonia of the testis To characterize the role of Sbf1 in animal development we generated mice in which both copies of the Sbf1 gene were disrupted. Disruption of the Sbf1 gene results in male infertility characterized by Sertoli cell vacuolation, germ cell apoptosis and azoospermia. The nullizygous phenotype in conjunction with high level expression of Sbf1 in premeiotic germ cells and Sertoli cells is consistent with a crucial role for Sbf1 in the transition from diploid to haploid spermatocytes. These studies provide the first detailed characterization of a putative pseudo-phosphatase and demonstrate an essential role for a myotubularin family protein in pathways that impinge upon growth control and differentiation.

ISBN: 0493628568Subjects--Topical Terms:

1017835
Biology, Animal Physiology.

Molecular and genetic characterization of the roles of the Sbf1 pseudo-phosphatase in growth control and development.
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520 $a The myotubularin family consists of a highly conserved group of proteins that have been linked to heritable human diseases and characterized as phosphoinositide phosphatases. Sbf1, originally identified by virtue of its interaction with SET domain/histone methyltransferase proteins, is a member of the myotubularin family. It is unique however in that it lacks phosphatase activity due to evolutionarily conserved amino acid changes in its catalytic pocket. Herein, we characterize the properties of Sbf1. Structural analyses of wildtype reveal that it is a cytoplasmic protein, however N-terminal mutations partially localize Sbf1 to the nucleus and lead to oncogenic transformation in tissue culture. In addition, oncogenically active forms of Sbf1 are capable of interacting with and modulating the function of SUV39H1, a SET domain protein that possesses histone methyltransferase activity. Sbf1 perturbs the transcriptional repression, cell growth inhibition and nuclear localization of SUV39H1 in a phosphorylation-dependent manner. Sbf1 is highly expressed in both Sertoli cells and spermatogonia of the testis To characterize the role of Sbf1 in animal development we generated mice in which both copies of the Sbf1 gene were disrupted. Disruption of the Sbf1 gene results in male infertility characterized by Sertoli cell vacuolation, germ cell apoptosis and azoospermia. The nullizygous phenotype in conjunction with high level expression of Sbf1 in premeiotic germ cells and Sertoli cells is consistent with a crucial role for Sbf1 in the transition from diploid to haploid spermatocytes. These studies provide the first detailed characterization of a putative pseudo-phosphatase and demonstrate an essential role for a myotubularin family protein in pathways that impinge upon growth control and differentiation.
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