PERCHE' IL SONNO REGOLARE AIUTA A PREVENIRE IL CANCRO?
INTRODUCTION
Chronic sleep deprivation perturbs the circadian clock and increases susceptibility to cancer.
Increased inflammation is one of the common underlying mechanisms of this disease, thus raising a hypothesis that circadian-oscillator components may regulate immune response.
MOLECULAR MECHANISM
The hypothalamic suprachiasmatic nucleus (SCN) functions as a master circadian oscillator, which controls behaviors. The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/CLOCK. heterodimers activate the expression of the PERIOD. and CRYPTOCHROME. genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/CLOCK completing the feedback loop.
Characterization of the core mammalian clock component, NPAS2, as a REV-ERBalpha/RORalpha target gene,2010.
WHAT HAPPENS WHEN CRY IS MISSING?
In the study of Rajesh Narasimamurthya et all. is proposed that both PKA and IKK2–IkBa-dependent phosphorylation of NF–kB contributes to increased activation of inflammatory cytokines, for example IL-6,
in Cry1-/-;Cry2-/- fibroblasts.
1)PKA:
Circadian clock–controlled expression of CRYproteins regulate the production of cAMP.
Temporally gated oscillations of cAMP levels and resultant PKA activity temporally modulates the basal activation state of the NF–κB pathway and may explain the well-described circadian rhythms in immune responses in mammals: the hypothesis is that when CRY proteins are present they bind to adenylyl cyclase and downregulate cAMP production In the absence of CRY, inhibition on adenylyl cyclase is relieved, which subsequently leads to increased cAMP production and PKA activation that cause increased phosphorylation of p65 at S276, ultimately resulting in activation of its target genes such as IL-6.
2)IKK2:
In Cry1−/−;Cry2−/− fibroblasts are observed increased levels of TNF-α and of IKK2.
It seems that the most likely initiator of phosphorylation and activation of IKK2 signaling complex in Cry1−/−;Cry2−/− cells is the increased activation of TNF-α (a well-known activator of IKK2 complex).
This activated IKK2 complex subsequently leads to phosphorylation and degradation of IκBα, which in turn cause increased p65 accumulation into the nucleus and high level of
DNA binding activity, ultimately resulting in increased expression of NF–κB. target genes such as IL-6.
Circadian clock protein cryptochrome regulates the expression of proinflammatory cytokines,2012.
CONCLUSION
The results indicate that an arrhythmic clock system, induced by the absence
of CRY proteins, alone is sufficient to increase the stress levels of cells leading to constant expression of inflammatory cytokines and causing a low-grade chronic inflammatory status and Cry-deficient cells could be a good model system to study this phenomenon.
Moreover, people exposed to frequent circadian clock disturbances, such as night-shift workers, are increasingly susceptible to this disease.
