Inosine-5′-Monophosphate Dehydrogenase Is a Rate-determining Factor for p53-dependent Growth Regulation

Abstract

We have proposed that reduced activity of inosine-5Ј-monophosphate dehydrogenase (IMPD; IMP:NAD oxidoreductase, EC 1.2.1.14), the rate-limiting enzyme for guanine nucleotide biosynthesis, in response to wild-type p53 expression, is essential for p53-dependent growth suppression. A gene transfer strategy was used to demonstrate that under physiological conditions constitutive IMPD expression prevents p53-dependent growth suppression. In these studies, expression of bax and waf1, genes implicated in p53-dependent growth suppression in response to DNA damage, remains elevated in response to p53. These findings indicate that under physiological conditions IMPD is a rate-determining factor for p53-dependent growth regulation. In addition, they suggest that the impd gene may be epistatic to bax and waf1 in growth suppression. Because of the role of IMPD in the production and balance of GTP and ATP, essential nucleotides for signal transduction, these results suggest that p53 controls cell division signals by regulating purine ribonucleotide metabolism. INTRODUCTIONBeyond being the basic units of nucleic acids, nucleotides are ubiquitous molecular regulators. Nucleotides modulate diverse cellular processes by noncovalent allosteric regulation; covalent chemical activation via cleavage of high-energy phosphate bonds; covalent transfer of modulatory phosphate moieties; and providing the high energy output of phosphate bond cleavage for macromolecular conformational changes (Lehninger, 1975). Although many of the processes controlled by nucleotides are specific to their own biosynthesis and metabolism, they regulate a variety of other cellular processes as well (Lehninger, 1973;Criss and Pradhan, 1976;Pall, 1985).Adenine and guanine ribonucleotides are the most frequently used nucleotides for molecular regulation, functioning to modulate important biochemical reactions in all aspects of cell function (Pall, 1985). Our interest in ATP and GTP as molecular regulators relates to their function as essential components of growth signal transduction pathways. Interestingly, in cellular signaling, ATP-dependent and GTP-dependent mechanisms appear to be restricted to one of two distinct phosphate cleavage reactions. ATP mechanisms employ covalent phosphoryltransfer (reviewed in Sibley et al., 1987;Aaronson, 1991;Cantley et al., 1991;Hunter, 1995), whereas GTP mechanisms use phosphate hydrolysis (reviewed in Reed, 1990;Simon et al., 1991;Hall, 1992;Chant and Stowers, 1995). Phosphoryltransfer modifies the catalytic or association properties of signaling molecules, whereas the energy of phosphate hydrolysis fuels structural rearrangements that lead to activation of GTP-bound proteins. Effectors of the balance of these distinct regulatory mechanisms may be important factors for integrated regulation of cellular growth signals.Given the importance of ATP and GTP in signal transduction, their metabolism may be an important factor for cellular signaling (Pall and Robertson, 1988;Sherley, 1991). However, effects of nucleotide metabolism...

Guanosine supplementation reduces apoptosis and protects renal function in the setting of ischemic injury

“…The exact mechanism is unknown, but two hypotheses have been proposed: first is the small size of the GTP pools compared with ATP pools (20,21). In most cells, the GTP/ATP ratio is around 1:5, and thus even minor reductions in GTP could be rate limiting for nucleic acid synthesis and hence trigger apoptosis.…”

The cellular response to p53: the decision between life and death

“…Similar correlation has been recently observed in the collaboration between p53 and pRb in the induction of apoptosis (Hsieh et al, 1999). Among the many genes that can be repressed by p53, bcl-2, IGF-1R, microtubule-associated protein-4 (MAP4), inosine-5'-monophosphate dehydrogenase (IMPD) and presenilin-1 are the most relevant since they can attenuate the apoptotic activity of p53 (Liu et al, 1998;Roperch et al, 1998;Vogt Sionov and Haupt, 1998). Moreover, p53 represses ribosomal gene transcription (Budde and Grummt, 1999) and inhibits RNA polymerase III-directed transcription (Cairns and White, 1998).…”

Transcription Initiation of the Yeast IMD2 Gene Is Abolished in Response to Nutrient Limitation through a Sequence in Its Coding Region

“…1B). Moreover, in mammalian cells, there is a tight relationship between IMPDH activity and the replicative state of the cell, and the p53 antiproliferative role depends on a correct control of IMPDH levels (16). We believe that the nutrient response of the GMP biosynthesis genes could well be an important signal for stationary-phase establishment rather than just a consequence of growth arrest.…”

“…It is indeed well documented that quiescent or differentiated cells have low IMPDH levels, while dividing cells have high levels of IMPDH (see, for example, references 2, 14, 19, and 29 for reviews). Furthermore, the overexpression of IMPDH can bypass the antiproliferative effect of p53, indicating that correct control of IMPDH levels is essential for the antiproliferative role of p53 (16). We therefore studied the regulation of the yeast GMP synthesis pathway in response to growth phase.…”