Subnuclear organization and trafficking of regulatory proteins: Implications for biological control and cancer

The regulated and regulatory components that interrelate nuclear structure and function must be experimentally established. A formidable challenge is to define further the control of transcription factor targeting to acceptor sites associated with the nuclear matrix. It will be important to determin e whether acceptor proteins are associated with a pre-existing core-filamen t structural lattice or whether a compositely organized scaffold of regulat ory factors is dynamically assembled. An inclusive model for all steps in t he targeting of proteins to subnuclear sites cannot yet be proposed. Howeve r, this model must account for the apparent diversity of intranuclear targe ting signals. It is also important to assess the extent to which regulatory discrimination is mediated by subnuclear domain-specific trafficking signa ls. Furthermore, the checkpoints that monitor subnuclear distribution of re gulatory factors and the sorting steps that ensure both structural and func tional fidelity of nuclear domains in which replication and expression of g enes occur must be biochemically and mechanistically defined. There is emer ging recognition that placement of regulatory components of gene expression must be temporally and spatially coordinated to facilitate biological cont rol. The consequences of breaches in nuclear structure-function relationshi ps are observed in an expanding series of diseases that include cancer [Wei s et at., 1994; Rogaia et al., 1997; Yano et at., 1997; Rowley, 1998; Zeng et al., 1998; McNeil et al., 1999; Tao and Levine, 1999a] and neurological disorders [Skinner et al., 1997]. As the repertoire of architecture-associa ted regulatory factors and cofactors expands, workers in the field are beco ming increasingly confident that nuclear organization contributes significa ntly to control of transcription. To gain increased appreciation for the co mplexities of subnuclear organization and gene regulation, we must continue to characterize mechanisms that direct regulatory proteins to specific tra nscription sites within the nucleus so that these proteins are in the right place at the right time. (C) 2001 Wiley-Liss, Inc.