AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |
Back to Blog
Properties of parallel lines gsp54/29/2023 Interestingly, the frequency of PI3K-increases at the RNA and protein levels exceeds those at the DNA level, suggesting that copy-number-independent mechanisms also regulate PI3K levels in ovarian cancer. Inhibition of PI3K decreases in vivo growth of ovarian cancer ( Hu et al., 2000). ![]() Approximately 40% of ovarian cancers show increased copy numbers at 3q26, which contains PIK3CA ( Iwabuchi et al., 1995 Shayesteh et al., 1999 Suzuki et al., 2000). The focus of our studies is the p110α catalytic subunit of type 1A PI3Ks, because the PIK3CA gene is frequently amplified as well as its expression increased at the RNA and protein level in ovarian cancer ( Shayesteh et al., 1999). ![]() In its active form, PI3K is a heterodimer of a catalytic and a regulatory subunit. Phosphorylation of membrane phosphatidylinositols (PtdIns) by PI3K is essential in the control of many cellular functions ( Toker and Cantley, 1997). In these promoters, the repression appears to be mediated either through physical interaction of p53 with activating transcription factors ( Kanaya et al., 2000 Sun et al., 1999), through direct interaction of p53 with TATA-binding protein ( Farmer et al., 1996 Seto et al., 1992 Subbaramaiah et al., 1999 Truant et al., 1993) or by direct binding of p53 to its consensus sequence ( Budhram-Mahadeo et al., 1999 Hoffman et al., 2002 Johnson et al., 2001 Lee et al., 1999), in which case repression is mediated via deactivation of adjacent factors and not directly through p53 binding ( Budhram-Mahadeo et al., 1999). Mechanisms of p53-mediated transrepression remain poorly understood because of the lack of a p53 consensus binding site within a number of repressed promoters ( May and May, 1999). This binding site forms four repeats of the pentamer 5′-PuPuPu-C-3′ alternating between the positive and negative strands of the DNA duplex ( McLure and Lee, 1998), suggesting that p53 binds DNA as a homotetramer ( Friedman et al., 1993). A consensus p53-binding site has been defined that comprises two copies of the sequence 5′-PuPuPu-CG-PyrPyrPyr-3′ separated by 0-13 nucleotides ( el-Deiry et al., 1992). Inactivation of p53 appears to be an early step in ovarian carcinogenesis ( Deligdisch et al., 1995 Schlosshauer et al., 2003) and results most commonly from mutations, but also from export from nuclei ( O'Brate and Giannakakou, 2003), mutations in proteins regulating p53 activity, overexpression of MDM2 or loss of ARF. In response to DNA damage, p53 is imported into the nucleus, binds to target genes and alters their transcription ( Chehab et al., 1999 Kubbutat et al., 1997 Mayo and Donner, 2001 Shieh et al., 1999 Unger et al., 1999 Zhou et al., 2001). P53 regulates genes involved in cell cycle arrest and apoptosis. The demonstration that p53 binds directly to the PIK3CA promoter and inhibits its activity identifies a novel mechanism whereby these two mediators regulate cellular functions, and whereby inactivation of p53 and subsequent upregulation of PIK3CA might contribute to the pathophysiology of ovarian cancer. Conversely, overexpression of p53 by adenoviral infection and activation of p53 by γ-irradiation both diminished p110α protein levels in normal OSE and ovarian cancer cells. Conditional suppression of functional p53 increased p110α transcripts, protein levels and PI3K activity in immortalized, non-tumorigenic ovarian surface epithelial (OSE) cells, the precursors of ovarian carcinoma. ![]() ![]() We identified two alternate PIK3CA promoters and showed direct binding of and transcriptional inhibition by p53 to one of these promoters. We investigated molecular mechanisms underlying interactions between these two mediators and their possible roles in ovarian tumorigenesis. Inactivation of the transcription factor and tumor suppressor p53, and overexpression or mutational activation of PIK3CA, which encodes the p110α catalytic subunit of phosphatidylinositol-3-kinase (PI3K), are two of the most common deleterious genomic changes in cancer, including in ovarian carcinomas.
0 Comments
Read More
Leave a Reply. |