Postdoctoral Position Available

Gary Stein, Ph.D.

Academic Role: Professor

Faculty Appointment(s) In:
   Cell Biology

Other Affiliation(s):
   Cancer Center

  

Regulation of Cell Cycle and Tissue-Specific Genes Controlling Proliferation and Differentiation in Biological Control and Cancer

The central theme of our research program has been to discover mechanisms controlling proliferation and differentiation in mammalian cells with emphasis on compromised regulation that is linked with disease.  We pioneered characterization of transcriptional regulation that mediates cell cycle control.  The laboratory is investigating molecular mechanisms regulating gene expression that controls competency for cell cycle progression at the G1/S phase transition in normal and tumor cells and for an abbreviated pluripotent cell cycle in human embryonic stem cells.  A second field in which our laboratory is making a major impact is skeletal biology, where we established the foundation for addressing bone tissue specific gene expression.  Current initiatives include microRNA-mediated control and molecular, cellular, biochemical and in vivo genetic parameters of skeletal development and bone remodeling, aberrations that accompany the onset and progression of skeletal disease, as well as perturbations related to breast and prostate cancer metastasis to bone.  Our research group has been instrumental in defining functional relationships between subnuclear organization of regulatory proteins and gene expression.  We have made important contributions to mechanisms that support combinatorial organization and assembly of regulatory machinery for gene expression in nuclear microenvironments and epigenetic control of cell fate and lineage commitment in biological control and cancer.  The architectural parameters of regulatory networks that are obligatory for fidelity of gene expression are being clarified as a basis for therapeutic strategies with high specificity and reduced off target effects.

Figure

Runx transcription factors associated with chromosomes and mitotic apparatus

Recent Publications

Young DW, Hassan MQ, Pratap J, Galindo M, Zaidi SK, Lee S, Yang X, Xie R, Javed A, Underwood J, Furcinitti P, Imbalzano AN, Penman S, Nickerson JA, Montecino M, Lian JB, Stein JL, van Wijnen AJ, Stein GS.  (2007) Mitotic occupancy and lineage-specific transcriptional control of rRNA genes by Runx2.  Nature, 445(25):442-446. 

Zaidi SK, Young DW, Javed A, Pratap J, Montecino M, van Wijnen AJ, Lian JB, Stein JL, Stein GS   (2007) Nuclear microenvironments in biological control and cancer.  Nature Reviews Cancer, 7:455-463.

Ghule PN, Dominski Z, Yang X, Marzluff WF, Becker KA, Harper JW, Lian JB, Stein JL, van Wijnen AJ, Stein GS. (2008) Staged assembly of histone gene expression machinery at subnuclear foci during the abbreviated cell cycle of human embryonic stem cells. Proc Natl Acad Sci USA, 105(44):16964–16969.

Zaidi SK, Dowdy CR, van Wijnen AJ,  Lian JB, Raza A, Stein JL, Croce CM, Stein GS. Altered Runx1 Subnuclear Targeting Enhances Myeloid Cell Proliferation and Blocks Differentiation by activating a miR-24/MKP-7/MAP Kinase Network.  Cancer Research, in press.

Holmes W F, Braastad CD, Mitra P, Hampe C, Doenecke D, Albig W, Stein JL, van Wijnen AJ, Stein GS.  (2005) Coordinate control and selective expression of the full complement of replication-dependent histone H4 genes in normal and cancer cells.  Journal of Biological Chemistry, 280(45)37400-37407.

Pratap J, Javed A, Languino LR, van Wijnen AJ, Stein JL, Stein GS, Lian JB.   (2005) The Runx2 osteogenic transcription factor regulates matrix metalloproteinase 9 in bone metastatic cancer cells and controls cell invasion.  Molecular and Cellular Biology, 25(19):8581-8591.

Miele A, Braastad CD, Holmes WF, Mitra P, Medina R, Xie R, Zaidi SK, Ye X, Wei Y, Harper JW, van Wijnen AJ, Stein JL, Stein GS.  (2005) HiNF-P directly links the cyclin E/CDK1/p220^NPAT pathway to histone H4 gene regulation at the G1/S phase cell cycle transition.  Molecular and Cellular Biology, 25:6140-6153.

Vradii D, Zaidi SK, Lian JB, van Wijnen AJ, Stein JL, Stein GS.  (2005) A point mutation in AML1 disrupts subnuclear targeting, prevents myeloid differentiation, and results in a transformation-like phenotype.  Proc Natl Acad Sci USA, 102:7174-7179.   

Javed A, Barnes GL, Pratap J, Antkowiak T, Gerstenfeld LC, van Wijnen AJ, Stein JL, Lian JB, Stein GS.  (2005) Impaired intranuclear trafficking of Runx2 (AML3/CBFA1) transcription factors in breast cancer cells inhibits osteolysis in vivo.  Proc Natl Acad Sci USA, 102(5):1454-1459.  

Young, D.W., Hassan M.Q., Yang, X.-Q., Galindo, M., Javed, A., Zaidi, S.K., Furcinitti, P., Lapointe, D., Montecino, M., Lian, J.B., Stein, J.L., van Wijnen, A.J., Stein, G.S.  (2007) Mitotic retention of gene expression patterns by the cell fate determining transcription factor Runx2.  Proc Natl Acad Sci USA, 104:3189-3194.  

Xie R, Medina R, Zhang Y, Hussain S, Colby J, Ghule P, Sundarajan S, Keeler M, Liu L-J, van der Deen M, Mitra P, Lian JB, Rivera J, Jones SN, Stein JL, van Wijnen AJ, Stein GS. (2009) The histone gene activator HINFP is a non-redundant Cyclin E/CDK2 effector during early embryonic cell cycles.  Proc Natl Acad Sci USA, Jul 28;106(30):12359-64. Epub 2009 Jul 9.

Potential Rotation Projects

Project #1: Molecular characterization of intranuclear targeting signals for the organization and assembly of regulatory machinery for cell cycle and tissue-specific gene expression in nuclear microenvironments of normal and tumor cells.

Project #2: Characterization of regulatory mechanisms controlling the pluripotent cell cycle of human embryonic cells and reprogrammed (induced pluripotent stem cells) cells.

Project #3: Utilization of intranuclear targeting signals for development of therapy with high specificity and minimal “off target” effects.

Project #4:  Investigation of mechanisms mediating mitotic retention of transcription factors in epigenetic regulation of cell fate and lineage commitment for biological control and cancer.

Academic Background

Academic Background
Ph.D., 1969, University of Vermont at Burlington

Interim Director, UMass/Memorial Cancer Center
Interim Director, Center for Stem Cell Biology & Regenerative Medicine

Office: S3-310
Phone: 508-856-5625
E-mail: Gary.Stein@umassmed.edu
Keywords: Stem Cell Biology, Cancer, Cell Cycle, Nuclear Architecture, Gene Regulation

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Postdoctoral Position Available Cell Cycle and Tissue-Specific Transcriptional Control Postdoctoral position available to investigate transcriptional regulation of cell cycle and tissue-specific genes. Emphasis is on developmental, growth factor and steroid hormone responsive control of proliferation and differentiation in normal and tumor cells. We are actively pursuing functional interrelationships between nuclear architecture (chromatin structure, nucleosome organization and the nuclear matrix) and expression of cell cycle and phenotype restricted genes (see Vaughan et al., Nature 377:362-365; Zeng et al., PNAS 94:6746-6751; Guo et al., PNAS 94:121-126). Please forward a curriculum vitae with 3 letters of reference to: Gary S. Stein Janet L. Stein Jane B. Lian Andre J. van Wijnen Department of Cell Biology University of Massachusetts Worcester Campus 55 Lake Ave. North Worcester, MA 01655