The fatty acid synthase gene is a conserved p53 family target from worm to human.
The discovery that the p53 family consists of three members (p53, p63 and p73) in vertebrates and of a single homolog in invertebrates has raised the challenge of understanding the functions of the ancestor and how they have evolved and differentiated within the duplicated genes in vertebrates. Here, we report that the fatty acid synthase (FAS) gene, encoding for a key enzyme involved in the biogenesis of membrane lipids in rapidly proliferating cells, is a conserved target of the p53 family throughout the evolution. We show that CEP-1, the C. elegans p53 homolog, is able to bind the two p53 family responsive elements (REs) identified in the worm fasn-1 gene. Moreover, we demonstrate that fasn-1 expression is modulated by CEP-1 in vivo, by comparing wild-type and CEP-1 knockout worms. In human, luciferase and chromatin immunoprecipitation assays demonstrate that TAp73alpha and DeltaNp63alpha, but not p53, TAp73beta and TAp63alpha bind the two p53 REs of the human FASN gene. We show that the ectopic expression of TAp73alpha and DeltaNp63alpha leads to an increase of FASN mRNA levels, while their silencing produces a decrease of FASN expression. Furthermore, we present data showing a correlation between DeltaNp63alpha and FASN expression in cellular proliferation. Of relevant importance is that fasn-1 is the first CEP-1 direct target gene identified so far in C. elegans and our results suggest a new CEP-1 role in cellular proliferation and development, besides the one already described in apoptosis of germ cells. These data confirm the hypothesis that the ancestral functions of the single invertebrate gene may have been spread out among the three vertebrate members, each of them have acquired specific role in cell cycle regulation.
Dipartimento di Biochimica e Biologia Molecolare Ernesto Quagliariello, Università degli Studi di Bari, Bari, Italy. annamaria.derchia@biologia.uniba.it
Anna Maria
AM
D'Erchia
Apollonia
A
Tullo
Konstantinos
K
Lefkimmiatis
Cecilia
C
Saccone
Elisabetta
E
Sbisà
D000818:Animals; D017173:Caenorhabditis elegans / Q000201:enzymology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D005091:Exons / Q000235:genetics; D064429:Fatty Acid Synthases / Q000235:genetics*; D005786:Gene Expression Regulation; D049751:Genome, Helminth / Q000235:genetics; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics; D015603:Keratinocytes / Q000378:metabolism / Q000528:radiation effects; D011485:Protein Binding; D020218:Response Elements / Q000235:genetics; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D014466:Ultraviolet Rays
C438244:CEP-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D064429:Fatty Acid Synthases