The effects of melatonin (Mel) and/or underfeeding (30% food restriction) on 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumorigenesis were examined in female Sprague-Dawley rats fed a semipurified diet. During the promotional phase of tumorigenesis, the animals began receiving either daily afternoon Mel (250 micrograms) or saline vehicle injections s.c. for 15 weeks. As compared with fed animals, underfed rats had a lower tumor incidence, tumor number and size while the latency to onset and regression of tumors was increased. Melatonin in fed rats moderately suppressed tumor incidence and number. However, the combination of Mel treatment and underfeeding caused the most marked inhibition of tumorigenesis as compared with either treatment alone. These results indicate that Mel administration and/or underfeeding during the promotional phase inhibit DMBA-induced mammary tumorigenesis perhaps via neuroendocrine and/or peripheral endocrine mechanisms.
Light deprivation by blinding or exposure to short photoperiod results in depressed prolactin (PRL) cell activity and gonadal regression in the male Syrian hamster after at least 42–56 days of treatment, and both of these events can be prevented if pineal removal accompanies light deprivation. In the present study, we investigated changes in PRL cell activity after 11 21 or 42 days of blinding by measuring changes in: (1) pituitary PRL mRNA levels; (2) newly synthesized pituitary PRL, and (3) pituitary-RIA-PRL. The purpose of this study was to characterize the early (i.e. prior to gonadal regression and loss of reproductive function) effects of light deprivation on PRL production in the pituitary gland of the male hamster, and to determine whether a reduction in PRL mRNA levels precedes the inhibition of PRL synthesis and storage. After 11, 21, and 42 days of blinding, PRL mRNA levels in the male hamster pituitary (relative PRL mRNA/pituitary) were significantly depressed compared to intact controls by 33, 41, and 65%, respectively. Pituitary PRL synthesis (dpm of 3H-PRL/pituitary) and RIA-PRL (µg PRL/pituitary) were significantly depressed (by 49 and 53%, respectively) only after 42 days of blinding. All of these statistically significant depressions were prevented when the surgical blinding procedure was accompanied by pineal removal. There were no differences in testicle, pituitary, or body weight as a result of treatment. These results support the hypothesis that light deprivation by blinding causes a pineal-dependent decline in PRL mRNA levels, which leads to a decrease in PRL synthesis and pituitary RIA-PRL.
All known actions of cAMP in the brain require cAMP-dependent protein kinase (cAMPdPK), which consists of regulatory (R) and catalytic (C) subunits (R2C2). Using homologous rat cDNAs for all known cAMPdPK subunit isoforms found in the brain (RIα, RIβ,RIIα, RIIβ, Cα, Cβ) we observe that, in the fetal rat brain from 12 days of gestation to birth, while a subunit (RIα, RIIα, Cα) mRNA levels are abundant, β subunit (RIβ, RIIβ, Cβ) mRNA levels increase from undetectable or very low levels to abundant levels. Furthermore, while a subunit mRNA levels are abundant in both primary neuronal and primary glial cultures, β subunit mRNA levels are very low (Cβ) or undetectable (RIβ, RIIβ) in primary glial cultures, but are abundant in primary neuronal cultures. Thus, prior to about 12 days of gestation, cAMP in the brain may act only via the a cAMPdPK subunits in neuronal and glial precursor cells. After 12 days of gestation, coincident with the onset of final cell division in neurons, β cAMPdPK subunits may also mediate the effects of cAMP predominantly in neurons.
A rat complementary DNA (cDNA) for the RI beta isoform of type I cyclic adenosine monophosphate (cAMP)-dependent protein kinase regulatory subunit was cloned and sequenced and was found to contain the entire protein coding and 3'-untranslated regions, with a single (ATTAAA) poly-adenylation site. The largest open reading frame was preceded by a short out-of-phase open reading frame, which is not seen in the corresponding mouse RI beta cDNA due to a single base substitution. The rat RI beta cDNA clone was 2,374 bases long and detected a rat mRNA of approximately 2.8 kilobases. Rat RI beta mRNA was abundant in adult rat brain and testis but was undetectable in other rat tissues. The rat RI beta cDNA also detected RI beta mRNA in mouse brain, but not mouse testis, from 10-week-old BALB/c or 10- and 6-week-old Swiss Webster mice. Thus, despite a 96% nucleotide identity in the coding region of RI beta in rat vs. mouse, there are at least two differences in these closely related species. First, there is a short open reading frame, which precedes the coding region in the rat but not the mouse. Second, unlike the mouse testis, the rat testis contains abundant levels of RI beta mRNA.
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