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BACKGROUND: P53 activation can trigger various outcomes, among them reversible growth arrest or cellular senescence. It is a live debate whether these outcomes are influenced by quantitative or qualitative mechanisms. Furthermore, the relative contribution of p53 to Ras-induced senescence is also matter of controversy. METHODOLOGY/PRINCIPAL FINDINGS: This study compared situations in which different signals drove senescence with increasing levels of p53 activation. The study revealed that the levels of p53 activation do not determine the outcome of the response. This is further confirmed by the clustering of transcriptional patterns into two broad groups: p53-activated or p53-inactivated, i.e., growth and cellular arrest/senescence. Furthermore, while p53-dependent transcription decreases after 24 hrs in the presence of active p53, senescence continues. Maintaining cells in the arrested state for long periods does not switch reversible arrest to cellular senescence. Together, these data suggest that a Ras-dependent, p53-independent, second signal is necessary to induce senescence. This study tested whether PPP1CA (the catalytic subunit of PP1alpha), recently identified as contributing to Ras-induced senescence, might be this second signal. PPP1CA is induced by Ras; its inactivation inhibits Ras-induced senescence, presumably by inhibiting pRb dephosphorylation. Finally, PPP1CA seems to strongly co-localize with pRb only during senescence. CONCLUSIONS: The levels of p53 activation do not determine the outcome of the response. Rather, p53 activity seems to act as a necessary but not sufficient condition for senescence to arise. Maintaining cells in the arrested state for long periods does not switch reversible arrest to cellular senescence. PPP1CA is induced by Ras; its inactivation inhibits Ras-induced senescence, presumably by inhibiting pRb dephosphorylation. Finally, PPP1CA seems to strongly co-localize with pRb only during senescence, suggesting that PP1alpha activation during senescence may be the second signal contributing to the irreversibility of the senescent phenotype.

Introduction: Sex differences in prenatal growth may contribute to sex-dependent programming effects on postnatal phenotype., Methods: We integrated for the first time phenotypic, histomorphological, clinico-chemical, endocrine and gene expression analyses in a single species, the bovine conceptus at mid-gestation., Results: We demonstrate that by mid-gestation, before the onset of accelerated growth, the female conceptus displays asymmetric lower growth compared to males. Female fetuses were smaller with lower ponderal index and organ weights than males. However, their brain:body weight, brain:liver weight and heart:body weight ratios were higher than in males, indicating brain and heart 'sparing'. The female placenta weighed less and had lower volumes of trophoblast and fetal connective tissue than the male placenta. Female umbilical cord vessel diameters were smaller, and female-specific relationships of body weight and brain:liver weight ratios with cord vessel diameters indicated that the umbilico-placental vascular system creates a growth-limiting environment where blood flow is redistributed to protect brain and heart growth. Clinico-chemical indicators of liver perfusion support this female-specific growth-limiting phenotype, while lower insulin-like growth factor 2 (IGF2) gene expression in brain and heart, and lower circulating IGF2, implicate female-specific modulation of key endocrine mediators by nutrient supply., Conclusion: This mode of female development may increase resilience to environmental perturbations in utero and contribute to sex-bias in programming outcomes including susceptibility to non-communicable diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Estrella, Gatford, Xiang, Javadmanesh, Ghanipoor-Samami, Nattrass, Shuaib, McAllister, Beckman, Thomsen, Clifton, Owens, Roberts, Hiendleder and Kind.)

The insulin-like growth factor (IGF) axis is fundamental for mammalian growth and development. However, no comprehensive reference data on gene expression across tissues and pre- and postnatal developmental stages are available for any given species. Here we provide systematic promoter- and splice variant specific information on expression of IGF system components in embryonic (Day 48), fetal (Day 153), term (Day 277, placenta) and juvenile (Day 365-396) tissues of domestic cow, a major agricultural species and biomedical model. Analysis of spatiotemporal changes in expression of IGF1, IGF2, IGF1R, IGF2R, IGFBP1-8 and IR genes, as well as lncRNAs H19 and AIRN, by qPCR, indicated an overall increase in expression from embryo to fetal stage, and decrease in expression from fetal to juvenile stage. The stronger decrease in expression of lncRNAs (average -16-fold) and ligands (average -12.1-fold) compared to receptors (average -5.7-fold) and binding proteins (average -4.3-fold) is consistent with known functions of IGF peptides and supports important roles of lncRNAs in prenatal development. Pronounced overall reduction in postnatal expression of IGF system components in lung (-12.9-fold) and kidney (-13.2-fold) are signatures of major changes in organ function while more similar hepatic expression levels (-2.2-fold) are evidence of the endocrine rather than autocrine/paracrine role of IGFs in postnatal growth regulation. Despite its rapid growth, placenta displayed a more stable expression pattern than other organs during prenatal development. Quantitative analyses of contributions of promoters P0-P4 to global IGF2 transcript in fetal tissues revealed that P4 accounted for the bulk of transcript in all tissues but skeletal muscle. Demonstration of IGF2 expression in fetal muscle and postnatal liver from a promoter orthologous to mouse and human promoter P0 provides further evidence for an evolutionary and developmental shift from placenta-specific P0-expression in rodents and suggests that some aspects of bovine IGF expression may be closer to human than mouse., Competing Interests: The authors have declared that no competing interests exist.