A Novel Transcriptional Repression Domain Mediates p21^WAF1/CIP1 Induction of p300 Transactivation

Abstract

The transcriptional coactivators p300 and CREB binding protein (CBP) are important regulators of the cell cycle, differentiation, and tumorigenesis. Both p300 and CBP are targeted by viral oncoproteins, are mutated in certain forms of cancer, are phosphorylated in a cell cycle-dependent manner, interact with transcription factors such as p53 and E2F, and can be found complexed with cyclinE-Cdk2 in vivo. Moreover, p300-deficient cells show defects in proliferation. Here we demonstrate that transcriptional activation by both p300 and CBP is stimulated by coexpression of the cyclin-dependent kinase inhibitor p21 WAF/CIP1 . Significantly this stimulation is independent of both the inherent histone acetyltransferase (HAT) activity of p300 and CBP and of the previously reported carboxyl-terminal binding site for cyclinE-Cdk2. Rather, we describe a previously uncharacterized transcriptional repression domain (CRD1) within p300. p300 transactivation is stimulated through derepression of CRD1 by p21. Significantly p21 regulation of CRD1 is dependent on the nature of the core promoter. We suggest that CRD1 provides a novel mechanism through which p300 and CBP can switch activities between the promoters of genes that stimulate growth and those that enhance cell cycle arrest.

Low p21Waf1/Cip1 protein level sensitizes testicular germ cell tumor cells to Fas-mediated apoptosis

“…Therefore, the reduced p21 protein levels in TGCT cells upon cisplatin treatment are predominantly due to the reduced p21 gene transcription in TGCTs. We can, however, not exclude the involvement of p21 proteasomal degradation, because p21 protein can also stimulate its own transcription by stimulating p300 transactivation of p53 (Snowden et al, 2000). Whether a reduced p53 transcriptional activity, as suggested above, is indeed responsible for the low p21 mRNA levels and not a decreased stability of the p21 mRNA has not been proven yet.…”

Cell cycle regulators and hematopoiesis

“…In the myeloid lineage, this may be related to direct protein ± protein interactions of p21 with C/EBPalpha (Harris et al, 2001) and with Stat 3 (Coqueret and Gascan, 2000), both of which are required for granulocytic di erentiation (McLemore et al, 2001;Wang et al, 1999). p21 also binds to the p300 transcriptional adapter and alters its activity (Coqueret and Gascan, 2000;Snowden et al, 2000) ; in addition, p21 binds directly to E2F and downmodulates E2F-1 dependent transcription (Delavaine and La Thangue, 1999); Genetic analysis suggests that this could be highly pertinent to di erentiation control (Muller et al, 2001). Hox genes are highly directive of di erentiation and may be among transcriptional targets modulated by p21-complexes .…”

The Cyclic Adenosine 5′-Monophosphate Response Element Modulator Suppresses IL-2 Production in Stimulated T Cells by a Chromatin-Dependent Mechanism

“…p300 contains a repression domain called cell cycle regulatory domain 1 (36), which is conserved in other proteins like the erythroblast transformation-specific domain and transcription factor ELK-1 as well, (37) and is able to actively repress transcription (36) in a manner that is dependent on the abundance of activating or repressing transcription factors. Furthermore, other mechanisms of transcriptional repression by CREM are possible and could include glycosylation or methylation of p300, CBP, or histones as well as a recruitment of inhibitors of transcription like histone deacetylating proteins (38 -40).…”