The chronobiology of the menstrual life sequence of American women

Seasonal variation in menarche, menstrual cycle length and menopause was investigated using Tremin Trust data. Too, self-reported hot flash data for women with natural and surgically-induced menopause were analyzed for rhythms.^ Menarche data from approximately 600 U.S. women born between 1940 and 1970 revealed a 6-month rhythm (first acrophase in January, double amplitude of 58%M). A notable shift from a December-January peak in menarche for those born in the 1940s and 1950s to an August-September peak for those born in the 1960s was observed. Groups of girls 8-14 and 15-17 yr old at menarche exhibited a seasonal difference in the pattern of menarche occurrence of about 6 months in relation to each other. Girls experiencing menarche during August-October were statistically significantly younger than those experiencing it at other times. Season of birth was not associated with season of menarche.^ The lengths of approximately 150,000 menstrual intervals of U.S. women were analyzed for seasonality. Menstrual intervals possibly disturbed by natural (e.g., childbirth) or other events (e.g., surgery, medication) were excluded. No 6- or 12-month rhythmicities were found for specific interval lengths (14-24, 25-31 and 32-56 days) or ages in relation to menstrual interval (9-11, 12-13, 15-19, 20-24, 25-39, 40-44 and 44 yr old and older).^ Hot flash data of 14 women experiencing natural menopause (NM) and 11 experiencing surgically-induced menopause (SIM) did not differ in frequency of hot flashes. Hot flashes in NM women exhibited 12- and 8-hr, but not 24-hr rhythmicities. Hot flashes in SIM women exhibited 24- and 12-hr, but not 8-hr, rhythmicities. Regardless of type of menopause, women with a peak frequency in hot flashes during the morning (0400 through 0950) were distinguishable from those with such in the evening (1600 through 2159).^ Data from approximately 200 U.S. women revealed a 6-month rhythm in menopause with first peak in May. No significant 12-month variation in menopause was detected by Cosinor analysis. Season of birth and age at menopause were not associated with season of menopause. Age at menopause declined significantly over the years for women born between 1907 and 1926, inclusive. ^

Functional analysis of p53 phosphorylation and a p53 hot spot mutation

The tumor suppressor p53 is a phosphoprotein which functions as a transcriptional activator. By monitoring the transcriptional activity, we studied how p53 functions is regulated in relation to cell growth and contact inhibition. When cells were arrested at G1 phase of the cell cycle by contact inhibition, we found that p53 transactivation function was suppressed. When contact inhibition was overridden by cyclin E overexpression which stimulates cell cycle progression, p53 function was restored. This observation led to the development of a cell density assay to study the regulation of p53 function during cell cycle for the functional significance of p53 phosphorylation. The murine p53 is phosphorylated at serines 7, 9, 12, 18, 37, 312 and 389. To understand the role of p53 phosphorylation, we generated p53 constructs encoding serine-to-alanine or serine-to-glutamate mutations at these codons. The transcriptional activity were measured in cells capable of contact inhibition. In low-density cycling cells, no difference in transcriptional activity was found between wild type p53 and any of the mutants. In contact-inhibited cells, however, only mutations of p53 at serine 389 resulted in altered responses to cell cycle arrest and to cyclin E overexpression. The mutant with serine-to-glutamate substitution at codon 389 retained its function in contact inhibited cells. Cyclin E overexpression in these cells induced p53 phosphorylation at serine 389. Furthermore, we showed that phosphorylation at serine 389 regulates p53 DNA binding activity. Our findings implicate that phosphorylation is an important mechanism for p53 activation.^ p53 is the most frequently mutated gene in human tumors. To study the mechanism of p53 inactivation by mutations, we carried out detailed analysis of a murine p53 mutation with an arginine-to-tryptophane substitution at codon 245. The corresponding human p53 mutation at amino acid 248 is the most frequently mutated codon in tumors. We showed that this mutant is inactive in suppressing focus formation, binding to DNA and transactivation. Structural analysis revealed that this mutant assumes the wild type protein conformation. These findings define a novel class of p53 mutations and help to understand structure-function relationship of p53. ^