Functional interactions between the retinoblastoma (Rb) protein and Sp-family members: superactivation by Rb requires amino acids necessary for growth suppression.

Abstract

The transient expression of the retinoblastoma protein (Rb) regulates the transcription of a variety of growth-control genes, including c-fos, c-myc, and the gene for transforming growth factor j31 via discrete promoter sequences termed retinoblastoma control elements (RCE) The human retinoblastoma susceptibility gene RB1 is believed to participate in the orchestration of orderly cell growth and/or differentiation (1). Deletion or mutational inactivation of RBJ is correlated with the genesis of a variety of human cancers including retinoblastoma, osteosarcoma, and carcinomas of the breast, bladder, and lung (2-6). The retinoblastoma protein (Rb) may also be sequestered by viral oncoproteins, such as simian virus 40 large tumor antigen, via conserved regions of the oncoproteins that are essential for viral-induced transformation (7-11).The Rb gene encodes a set of ubiquitously expressed nuclear phosphoproteins that are distinguished by their extent of posttranslational modification (3,(12)(13)(14). Given its nuclear localization and an associated nonspecific affinity for DNA, a role for Rb in the regulation of gene expression has been suggested (3, 12). This supposition was supported by experiments demonstrating that a 30-bp sequence within the c-fos promoter is a target of Rb function (15). This sequence, termed "retinoblastoma control element" (RCE), was shown to be necessary and sufficient for Rb-mediated transcription control. Subsequently, similar elements have been described within the promoters of a variety of genes that themselves encode growth regulatory molecules (16)(17)(18)(19)(20)(21)(22). Interestingly,The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.Kim et at (18) showed that the transcriptional response of a given RCE to Rb coexpression is cell-type dependent and may be stimulatory or inhibitory. While a mechanism for Rbmediated transcriptional regulation was not indicated by these experiments, recent evidence strongly suggests that Rb functions to regulate transcription via its physical interaction with sequence-specific DNA-binding proteins (23)(24)(25)(26)(27)(28)(29).The binding of viral oncoproteins to Rb occurs within a discrete portion of the Rb carboxyl terminus that is a "hotspot" for mutation in human cancers (2,3,(30)(31)(32)(33)(34)(35)(36). This region, often referred to as the Rb "pocket," is also the site of interaction of Rb with a variety of proteins that are believed to be targets of Rb function, including transcription factors E2F-1, ATF-2, and myoD (23, 25, 27, 28). The functional consequence of the formation of such complexes can be quite distinct. Rb forms cell-cycle-regulated complexes with E2F-1 and down-regulates E2F-dependent transcription in vivo (for a review, see ref. 23). In contrast, the formation of complexes between Rb and ATF-2 or myoD leads to an increase in ATF-2 or myoDmediated transcription (25,...

Glucosamine activates the plasminogen activator inhibitor 1 gene promoter through Sp1 DNA binding sites in glomerular mesangial cells.

“…There are 4 transcriptional activation domains in Sp1 that interact with transcriptional cofactors, including subunits of the TF II D and CRSP complexes (70)(71)(72)(73). Recognized interactions between Sp1 and Smads (74), AP-1 (78), retinoblastoma protein (60,76), cyclin D (70), CBP/p300 (through progesterone receptors) (77), or other Sp1 molecules to form higher-order multimers (71) could all have been affected by glucosamine and merit further investigation.…”

Overlapping Sp1 and AP2 binding sites in a promoter element of the lens-specific MIP gene

“…Therefore, Sp3 may play a role in modulating MIP gene expression in lens fibers or in repressing its expression in lens epithelium. It is interesting to note that the retinoblastoma gene product Rb interacts with Sp1 and Sp3 and synergistically activates Sp1-or Sp3-mediated transcription (56). As Rb plays a role in withdrawal from the cell cycle in differentiating lens fiber cells and MIP expression is markedly decreased in Rb -/-mice (57), it is tempting to speculate that the Sp1-Rb and/or Sp3-Rb interaction may provide a mechanism for activating MIP gene expression in the lens fibers.…”

Ring-Sp1 decoy oligonucleotide effectively suppresses extracellular matrix gene expression and fibrosis of rat kidney induced by unilateral ureteral obstruction

“…[17][18][19][20] Specifically, pRb stimulates the transcription of c-myc and c-fos through the binding of Sp1 to their promoter elements. [21][22][23] Thus, Sp1 factors are mainly involved in growth-related signal transduction pathways including apoptosis, angiogenesis, and tumorigenesis. 24,25 The transcription of TGF-b1 is regulated through Sp1 binding to GC-rich sites in the promoter.…”