Figure 2.

Role of oncogene and tumor suppressor genes in Ca²⁺ dependent RCD. (A) In normal cells, stressing stimuli (e.g., UV irradiation) induces the transfer of Ca²⁺ from ER to mitochondria, causing the transition of F1/FO ATP synthase to mPTP, hence the engagement of RCD. (B) Elevation of Bcl-2 or H-RAS expression causes the reduction of Ca²⁺ content into ER lumen, causing an impaired Ca²⁺ transfer to mitochondria which fail to properly engage mPTP and RCD. (C) AKT activation causes the phosphorylation of Ip3R3 and the MCU member MICU1, making both channels less permeable to Ca²⁺. Similarly, FBXL impairs Ip3R3 stability, and favoring its degradation. Both mechanisms result in a lower Ca²⁺ transfer, while leaving ER Ca²⁺ content unchanged. (D) The oncosuppressor genes PTEN and PML counteract the effect of AKT and FBXL, by dephosphorylating and stabilizing Ip3R3. This potentiates the Ca²⁺ accumulation to mitochondria, empowering mPTP opening. (E) p53 directly interacts with SERCA, favoring its Ca²⁺ pumping activity within ER lumen. This results in favored Ca²⁺ transfer, mPTP opening and RCD.