p53 Regulates Caveolin Gene Transcription, Cell Cholesterol, and Growth by a Novel Mechanism

Abstract

Transcription of the human caveolin gene, directed by a TATA-less promoter, is downregulated in actively dividing cells during S-phase, together with free cholesterol (FC) efflux. It is upregulated by medium low density lipoprotein FC levels in quiescent cells. In this study, a common mechanism has been identified to coordinate the growth- and FC-dependent expression of caveolin. In human skin fibroblasts, transcription factors E2F/DP-1 and Sp1 bound to adjacent consensus sites at -151 to -138 bp of the caveolin promoter DNA sequence in a complex stabilized by tumor suppressor protein p53. Wild-type p53 also bound directly to DNA to a caveolin promoter sequence containing two consensus half-sites (-292 to -283 bp and -273 to -264 bp) for this transcription factor. SREBP-1, previously identified as a transcriptional regulator of caveolin expression in response to FC, mediated its effect via the same E2F/Sp1 site. Overexpression of E2F or p53 increased E2F binding to the -148 to -141 bp site, increased FC efflux, and inhibited cell division. The mutant protein p53(143V-->A) was inactive. Okadaic acid, previously shown to inhibit growth, FC efflux, and caveolin expression, inhibited E2F/Sp1 binding, while higher concentrations of extracellular FC increased it. The present findings provide a molecular link between the cell cycle and FC homeostatic effects of caveolin. These results also describe a novel mechanism of action for p53 in a TATA-less gene promoter and provide further evidence for a significant regulatory role for FC in cell cycle progression.

Neuron-targeted Caveolin-1 Protein Enhances Signaling and Promotes Arborization of Primary Neurons

“…Other evidence supports a role for free cholesterol and membrane/lipid rafts in formation of neuronal synapses and in the signaling and protection of neurons (7,9,12,40,41). Moreover, as an essential component of rafts, cholesterol and changes in the cellular content of cholesterol can affect Cav expression (42,43). For example, BDNF, which is essential for synaptic function and development, stimulates cholesterol biosynthesis and increases membrane/lipid rafts and Cav expression in cortical and hippocampal neurons (44).…”

Transcriptional Repression of Caveolin-1 (CAV1) Gene Expression by GATA-6 in Bladder Smooth Muscle Hypertrophy in Mice and Human Beings

“…48 CAV1 is transcriptionally induced in colon cancer cells in response to conditional expression of a full-length adenomatous polyposis coli (APC) gene. The induction of caveolin-1 by APC is mediated by both FOXO1a, a member of the forkhead box family of transcription factors, and c-myc.…”

The class II tumour suppressor gene H-REV107-1 is a target of interferon-regulatory factor-1 and is involved in IFNγ-induced cell death in human ovarian carcinoma cells

“…Impairment of class I tumour suppressors such as p53 can cause a diminished class II gene expression. For example, wild-type p53 stimulates the expression of the angiogenesis inhibitor thrombospondin (Dameron et al, 1994), the signalling regulator caveolin-1 (CAV1; Bist et al, 2000) and the serine protease inhibitor maspin (Zou et al, 2000). Mutational inactivation or loss of p53 results in the loss of transcriptional activator function and tumour suppressor gene down-regulation.…”