Intranuclear trafficking of transcription factors: Requirements for vitamin D‐mediated biological control of gene expression

Abstract

The architecturally associated subnuclear organization of nucleic acids and cognate regulatory factors suggest functional interrelationships between nuclear structure and gene expression. Mechanisms that contribute to the spatial distribution of transcription factors within the three-dimensional context of nuclear architecture control the sorting of regulatory information as well as the assembly and activities of sites within the nucleus that support gene expression. Vitamin D control of gene expression serves as a paradigm for experimentally addressing mechanisms that govern the intranuclear targeting of regulatory factors to nuclear domains where transcription of developmental and tissue-specific genes occur. We will present an overview of molecular, cellular, genetic, and biochemical approaches that provide insight into the trafficking of regulatory factors that mediate vitamin D control of gene expression to transcriptionally active subnuclear sites. Examples will be presented that suggest modifications in the intranuclear targeting of transcription factors abrogate competency for vitamin D control of skeletal gene expression during development and fidelity of gene expression in tumor cells.

Overexpression of theRADICAL-INDUCED CELL DEATH1(RCD1) Gene of Arabidopsis Causes Weakrcd1Phenotype with Compromised Oxidative-Stress Responses

“…15) At present, each of various functions of nucleus, including transcription, processing, DNA replication and chromatin remodeling, is thought to be organized into discrete subnuclear foci, though study of their function and architecture is just beginning. 16) Observation of RCD1-GFP speckles might indicate significance in nuclear functions. It might be informative that mammalian PARPs have been shown to be localized in the nucleolus, a distinct intranuclear domain.…”

Quantitative signature for architectural organization of regulatory factors using intranuclear informatics

“…Significant alterations in subnuclear organization were observed for the Y428A, Y433A and ∆C mutations. It has been proposed that nuclear microenvironments represent the steady state local accumulation of proteins resulting from dynamic molecular interactions providing threshold concentrations of regulatory factors for combinatorial control (Stein et al, 2000a;Stein et al, 2000b;Misteli, 2001;Stein et al, 2003). Consistent with this concept, the Y428A mutant, which has a significant reduction in the mean and variability in domain size (Fig.…”

“…The architectural organization of nucleic acids and cognate factors in subnuclear microenvironments is linked to gene regulation, replication and repair (Stein et al, 2000a;Stein et al, 2000b;Lemon and Tjian, 2000;Dundr and Misteli, 2001;Iborra and Cook, 2002;Spector, 2003;Stein et al, 2003). Spatio-temporal changes in this subnuclear organization accompany cell cycle progression and cell differentiation (Ma et al, 1998;Francastel et al, 2000).…”

“…It is becoming increasingly evident that regulatory parameters of gene expression are operative within a higher-order subnuclear organization of nucleic acids and regulatory proteins. Observations made by epifluorescence and confocal microscopy have provided the initial insight into assembly of nuclear microenvironments that support the combinatorial compartmentalization of regulatory factors and chromosomal domains (Cook, 1999;Stein et al, 2000a;Stein et al, 2000b;Stein et al, 2003;Spector, 2003). Quantitative strategies are necessary to mechanistically associate the subnuclear organization of regulatory factors with biological control.…”

The Crucial Role of c-Src Tyrosine Kinase in Bone Metabolism

“…The Runx transcription factors and their co-regulators control cell differentiation and lineage commitment (Westendorf & Hiebert, 1999) by influencing the functional architecture of target gene promoters (Stein et al, 2000). Runx proteins are directed to subnuclear domains through the Cterminal nuclear matrix-targeting signal (NMTS) and interact with the DNA through the Nterminal runt homology domain (Zaidi et al, 2001).…”