PhD 1986 University of Tübingen and Max-Planck
Institute for Immunobiology, Freiburg, Germany
bm3f@virginia.edu
| Beyond Tumor suppression: Possible involvement of p53 in determining body size, reproductive fertility and time course of aging. With the help of an N-terminal deletion mutant of p53, called p44, which naturally occurred in mice, we are trying to get insights into the complex regulatory functions exerted by p53. The mutant under study is missing the first 40 amino acids of the p53 protein, which comprise molecular domains important for p53 stability as well as transactivating and transrepressing functions. The domains important for DNA-binding, tetramerization and other regulatory sites are conserved. The p44 mutant can therefore integrate into heterotetrameric complexes with endogenous p53 and influence various functions of the p53 complex. Among other consequences, the stability of the heterotetrameric complex as well its DNA binding affinity is significantly increased. When expressed as a transgene and bred to homozygosity on a genetic background of normal endogenous p53, mice develop a highly interesting phenotype: they grow only to half the body size of their normal or heterozygous littermates, they become prematurely infertile (4-6 months) and age prematurely showing health complications of old age (>8 month). Detailed studies of embryogenesis and development of these mice undertaken in our lab show that the p53 mutation visibly affects and slows down embryonic development already from the blastocyst stage on. Mouse embryo fibroblasts explanted from these mice show slow proliferation and replicative senescence after only a few divisions. Also markedly affected are male germ cells and hence spermatogenesis leading to steady loss of germ cells resulting in a "Sertoli-only" phenotype at increasing age. This suggests that the stem cell pools of the hematopoetic system as well as of the germ line are affected. To gain insight into the molecular mechanisms, which give rise to the complex phenotype of these mice, we started out studying the IGF-1 (Insulin-like Growth Factor) pathway in mouse embryo fibroblasts as the major signaling pathway controlling embryonic and postnatal growth, replication and survival of cells in the mouse. We monitored the IGF-1 induced phosphorylation cascade and the protein levels of the molecules involved in the IGF-1 pathway and its main regulator PTEN. We find pronounced and unexpected effects of the p44 mutant on IGF-1, PTEN and cell cycle control pathways. We hope that this study might help our understanding of how p53 is linking extracellular cues to cellular metabolism and cell cycle control. It might also help us to understand how a molecular imbalance caused by a mutation of p53 can affect body size, fertility, aging and general health.
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