Supervisors info:
ΤΡΟΥΓΚΑΚΟΣ ΙΩΑΝΝΗΣ, ΚΑΘΗΓΗΤΗΣ, ΤΟΜΕΑΣ ΒΙΟΛΟΓΙΑΣ ΚΥΤΤΑΡΟΥ ΚΑΙ ΒΙΟΦΥΣΙΚΗΣ, ΤΜΗΜΑ ΒΙΟΛΟΓΙΑΣ, ΕΚΠΑ
Summary:
Abstract
Aging is characterized by the accumulation of damage and the consequent decline of cellular function, and is considered the major risk factor for cancer, cardiovascular disease, diabetes, and neurodegenerative disorders (Halliwell et al., 2015). The cellular protein quality control is controlled by the proteostasis network: the UPP (Ubiquitin-Proteasome Pathway) and ALP (Autophagy-Lysosome Pathway) proteolytic pathways, which function declines with age (Wolff et al., 2014; Koga et al., 2011). Mitochondria provide energy to the cell and are the main source of reactive oxygen species (ROS). Several studies have shown that dysfunctional mitochondria and ROS production are involved in aging process (Edgar et al., 2009; Hiona et al., 2010).
Aim of this theses was the in vivo study of Ras and Cdc6 genes, which are involved in cancerogenesis, during aging.
According to our results, flies overexpressing Ras85Dv12 and Cdc6 induced high oxidative stress levels and additionally Ras85Dv12 flies displayed reduced mitochondria number. Furthermore, overexpression of Ras85Dv12 led to decreased 26S proteasome, as well as cathepsins B and L, activities. On the other hand, overexpression of the Cdc6 upregulated the activity of both UPP and ALP pathways. Overexpression of both genes led also to accumulation of DNA damage. Moreover, flies overexpressing Ras85Dv12 had a dramatic reduction of lifespan expectancy compared to control flies, differently from flies overexpressing Cdc6. To reduce oxidative stress levels, we overexpressed cncC in the background of Ras85Dv12 and Cdc6 flies. Activation of cncC decreased oxidative stress levels and DNA damage accumulation. Moreover, overexpression of cncC increased both proteasome and cathepsins B and L activities, but it did not improve flies’ overexpressing Ras85Dv12 and Cdc6 longevity. Furthermore, targeted overexpression of the Ras85Dv12 and Cdc6 in Drosophila melanogaster's eye highlighted their role in triggering cellular proliferation.
In conclusion, our in vivo study of Ras85Dv12 and Cdc6 genes, suggest that their overexpression can cause genomic instability, disrupted proteostasis, mitochondrial dysfunction, and uncontrolled proliferation, which comprise some of the hallmarks of cancer and aging.
Keywords:
Aging, Cancer, Proteostasis, Ras, Cdc6, cncC
