ASPECTS OF UTERINE CELL CYCLE REGULATION IN IMPLANTATION

Summary

Principal Investigator: SANJOY KUMAR DAS
Abstract: DESCRIPTION: (Adapted from the applicant's abstract) The process of embryo implantation is associated with uterine stromal cell decidualization, an event that is critical to the success of pregnancy. The decidualization process is characterized by stromal cell growth and transformation into decidual cells, and formation of stromal cell polyploidy which occurs due to endoreduplication without cell division. The process of cellular division is tightly regulated in the cell cycle at two particular checkpoints, G1-S and G2-M. Several cell cyclins (A, B, D and E type cyclins) are known to play key roles with regard to cellular growth in a phase specific manner during these transitions. In this regard, the PI has recently demonstrated that the upregulation of cyclin D3 is tightly associated with decidualization of the uterus. It is well accepted that the dynamic control of the cell cycle is executed by an interplay of cyclins, cyclin-dependent kinases (cdks) and cdk inhibitors (CKIs). The objectives of this revised application are to focus on the cell cycle regulators that participate in the onset and progression of decidualization aspects of the implantation process. The hypothesis is that cell cycle regulators are expressed in the uterus in a spatiotemporal manner and their coordinated interactions play key roles in these processes. The specific aims are: 1) To characterize the spatiotemporal expression of cyclins (A, B, D2 and E), cdks (cdk1, cdk2, cdk4 and cdk6) and CKIs (p27 and p21) in the periimplantation (days 1-8) uterus of wild-type mice; 2) To study the role of cell cycle molecules in decidualization and the effects of the EGF family of growth factors in this process; 3) To study the regulation and functional status of cdks, respective cyclins and CKIs in the uterus during implantation and decidualization in cyclin D2, D3 or p27 null mice; and 4) To assess the status of cyclins (A, B, D2, D3 and E), cdks (cdk1, cdk2, cdk4 and cdk6) and CKIs (p27 and p21) in the uteri of Hoxa-10 null mice. The investigators will characterize mRNA expression by Northern and in situ hybridization and protein expression by immunohistochemistry, Western blotting and immunoprecipitation. The functional activity of cyclin-cdk-CKI associated complexes will be determined by in vitro phosphorylation activity. The results obtained from these studies will provide important insights regarding the potential roles of key cell cycle regulators in uterine biology during implantation and decidualization. Since these processes are analogous to pseudomalignancy, the results should also provide basic information relevant to cancer biology.
Funding Period: 2001-02-15 - 2007-12-31
more information: NIH RePORT

Top Publications

  1. pmc Cooperative control via lymphoid enhancer factor 1/T cell factor 3 and estrogen receptor-alpha for uterine gene regulation by estrogen
    Sanhita Ray
    Division of Reproductive and Developmental Biology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee 37232 2678, USA
    Mol Endocrinol 22:1125-40. 2008
  2. pmc Increased level of cellular Bip critically determines estrogenic potency for a xenoestrogen kepone in the mouse uterus
    Sanhita Ray
    Department of Pediatrics, Division of Reproductive and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232 2678, USA
    Endocrinology 148:4774-85. 2007
  3. ncbi Proteomic analysis identifies immunophilin FK506 binding protein 4 (FKBP52) as a downstream target of Hoxa10 in the periimplantation mouse uterus
    Takiko Daikoku
    Department of Pediatrics and Cancer Biology, Division of Reproductive and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
    Mol Endocrinol 19:683-97. 2005
  4. pmc Maternal heparin-binding-EGF deficiency limits pregnancy success in mice
    Huirong Xie
    Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
    Proc Natl Acad Sci U S A 104:18315-20. 2007
  5. ncbi Stage-specific integration of maternal and embryonic peroxisome proliferator-activated receptor delta signaling is critical to pregnancy success
    Haibin Wang
    Department of Pediatrics, Division of Reproductive and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
    J Biol Chem 282:37770-82. 2007
  6. pmc Fatty acid amide hydrolase deficiency limits early pregnancy events
    Haibin Wang
    Department of Pediatrics, Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
    J Clin Invest 116:2122-31. 2006
  7. ncbi Bip is a molecular link between the phase I and phase II estrogenic responses in uterus
    Sanhita Ray
    Division of Reproductive and Developmental Biology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee 37232 2678, USA
    Mol Endocrinol 20:1825-37. 2006
  8. ncbi Conditional gene recombination by adenovirus-driven Cre in the mouse uterus
    Haibin Wang
    Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee 37232 2678, USA
    Genesis 44:51-6. 2006
  9. ncbi Hoxa-10 deficiency alters region-specific gene expression and perturbs differentiation of natural killer cells during decidualization
    Mohammad A Rahman
    Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
    Dev Biol 290:105-17. 2006
  10. pmc Variation in commercial rodent diets induces disparate molecular and physiological changes in the mouse uterus
    Haibin Wang
    Department of Pediatrics, Division of Reproductive and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
    Proc Natl Acad Sci U S A 102:9960-5. 2005

Scientific Experts

  • SANJOY KUMAR DAS
  • Haibin Wang
  • Sudhansu K Dey
  • Sanhita Ray
  • Huirong Xie
  • Susanne Tranguch
  • Hao Zhang
  • Yong Guo
  • Takiko Daikoku
  • Fuhua Xu
  • Ping Li
  • Mohammad A Rahman
  • Lawrence J Marnett
  • Meiling Li
  • Xiaonan Hou
  • Philip J Kingsley
  • Limin Yue
  • Xiaofei Sun
  • Eisuke Mekada
  • Xiangxu Jia
  • Walter Wahli
  • Raymond N DuBois
  • Beatrice Desvergne
  • John P Lydon
  • Dingzhi Wang
  • Nora S Sanchez
  • Ryo Iwamoto
  • Francesco J DeMayo
  • Han E Zhou
  • Benjamin F Cravatt
  • Toshifumi Takahashi
  • Natsuo Ueda
  • David B Friedman
  • Harald H O Schmid
  • David F Smith
  • Gregory Hanley
  • Hiroshi Nojima
  • Yasuo Okamoto

Detail Information

Publications13

  1. pmc Cooperative control via lymphoid enhancer factor 1/T cell factor 3 and estrogen receptor-alpha for uterine gene regulation by estrogen
    Sanhita Ray
    Division of Reproductive and Developmental Biology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee 37232 2678, USA
    Mol Endocrinol 22:1125-40. 2008
    ..Collectively, these studies support a mechanism that integration of a nonclassically induced beta-catenin/Lef-1/Tcf-3 signaling with ERalpha is necessary for estrogen-dependent endogenous gene regulation in uterine biology...
  2. pmc Increased level of cellular Bip critically determines estrogenic potency for a xenoestrogen kepone in the mouse uterus
    Sanhita Ray
    Department of Pediatrics, Division of Reproductive and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232 2678, USA
    Endocrinology 148:4774-85. 2007
    ..Collectively, studies provide novel molecular evidence that Bip acts as a critical regulator to amplify estrogenic potency for a weak xenoestrogen kepone...
  3. ncbi Proteomic analysis identifies immunophilin FK506 binding protein 4 (FKBP52) as a downstream target of Hoxa10 in the periimplantation mouse uterus
    Takiko Daikoku
    Department of Pediatrics and Cancer Biology, Division of Reproductive and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
    Mol Endocrinol 19:683-97. 2005
    ..Collectively, these results and the female infertility phenotype of FKBP52 suggest that a Hoxa10-FKBP52 signaling axis is critical to uterine receptivity and implantation...
  4. pmc Maternal heparin-binding-EGF deficiency limits pregnancy success in mice
    Huirong Xie
    Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
    Proc Natl Acad Sci U S A 104:18315-20. 2007
    ..Our study provides genetic evidence that HB-EGF is critical for normal implantation. This finding has high clinical relevance, because HB-EGF signaling is known to be important for human implantation...
  5. ncbi Stage-specific integration of maternal and embryonic peroxisome proliferator-activated receptor delta signaling is critical to pregnancy success
    Haibin Wang
    Department of Pediatrics, Division of Reproductive and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
    J Biol Chem 282:37770-82. 2007
    ..This study is clinically relevant because deferral of on time implantation leads to spontaneous pregnancy loss, and defective trophoblast invasion is one cause of preeclampsia in humans...
  6. pmc Fatty acid amide hydrolase deficiency limits early pregnancy events
    Haibin Wang
    Department of Pediatrics, Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
    J Clin Invest 116:2122-31. 2006
    ..This study uncovers what we believe to be a novel regulation of preimplantation processes, which could be clinically relevant for fertility regulation in women...
  7. ncbi Bip is a molecular link between the phase I and phase II estrogenic responses in uterus
    Sanhita Ray
    Division of Reproductive and Developmental Biology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee 37232 2678, USA
    Mol Endocrinol 20:1825-37. 2006
    ..In conclusion, Bip is critical for coordinating estrogen-elicited biphasic responses and serves as a molecular link between ERalpha-independent and -dependent estrogenic responses in the uterus...
  8. ncbi Conditional gene recombination by adenovirus-driven Cre in the mouse uterus
    Haibin Wang
    Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee 37232 2678, USA
    Genesis 44:51-6. 2006
    ..These findings demonstrate the feasibility of achieving conditional expression or deletion of specific genes in uterine cells at desired times and physiological states...
  9. ncbi Hoxa-10 deficiency alters region-specific gene expression and perturbs differentiation of natural killer cells during decidualization
    Mohammad A Rahman
    Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
    Dev Biol 290:105-17. 2006
    ..Collectively, the results provide evidence that Hoxa-10 influences a host of genes and cell functions necessary for propagating normal decidual development during the post-implantation period...
  10. pmc Variation in commercial rodent diets induces disparate molecular and physiological changes in the mouse uterus
    Haibin Wang
    Department of Pediatrics, Division of Reproductive and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
    Proc Natl Acad Sci U S A 102:9960-5. 2005
    ....
  11. ncbi N-acylphosphatidylethanolamine-hydrolyzing phospholipase D is an important determinant of uterine anandamide levels during implantation
    Yong Guo
    Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
    J Biol Chem 280:23429-32. 2005
    ..The expression is well correlated with its activity and anandamide levels. This study is clinically relevant, since elevated anandamide levels in peripheral circulation are associated with spontaneous pregnancy failure in women...
  12. ncbi Cyclin G1 and cyclin G2 are expressed in the periimplantation mouse uterus in a cell-specific and progesterone-dependent manner: evidence for aberrant regulation with Hoxa-10 deficiency
    Limin Yue
    Division of Reproductive and Developmental Biology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
    Endocrinology 146:2424-33. 2005
    ....
  13. ncbi Cell cycle regulatory control for uterine stromal cell decidualization in implantation
    Sanjoy K Das
    Reproductive Sciences, Department of Pediatrics, Cincinnati Children s Hospital Medical Center, Cincinnati, Ohio 45229 3039, USA
    Reproduction 137:889-99. 2009
    ..This review will aim to address the currently available knowledge on interaction between growth factor/homeobox and cell cycle regulatory signaling in the progression of various aspects of decidualization...