The aforementioned genetic interaction between RB and Ras mined a new genetic interaction between RB and SREBP; this further allocated a new role to pRB in lipid metabolism, since SREBP are master regulators of lipogenic and steroidogenic genes.[10, 36] Indeed, in our initial study, pRb appeared to target many of the genes coding enzymes that participate in fatty acid and cholesterol biosynthesis. In their promoter, these genes possess either sterol regulatory elements (SRE) or E2F-binding consensus sequences or both (Fig. 4). Recently, a new regulator of SREBP has emerged. Mutated p53 directly binds to SREBP-2 and enhances its transactivation potential, thus contributing to the invasive morphology of breast cancer cells in 3D culture probably due to enhanced geranylgeranylation. SREBP transactivate most genes implicated in the mevalonate (MVA) pathway that governs farnesylation, geranylgeranylation and cholesterol synthesis (Fig. 4). This report, in addition to our own study, tightly linked two important tumor suppressors, pRB and p53, to the MVA pathway. Another regulator of SREBP is the PI3K/AKT signaling pathway. An activated AKT signal regulates the SCAP-mediated processing of SREBP precursors, and also attenuates ubiquitination of mature (nuclear) SREBP by inhibiting GSK3 function to phosphorylate mature SREBP. A recent study demonstrated that Lipin1, which is a substrate for mTORC1 kinase activity, eliminates mature SREBP from the nucleus. Lipin1 could also link SREBP and p53. One of the SREBP targets, fatty acid synthase (FASN), has also been identified to be a pRB transcriptional target. This product uses NADPH provided by the shunt from the glycolytic pathway (pentose phosphate pathway) and fuels carbon sources into the MVA pathway. An elevated FASN level during tumor progression might well explain the ‘lipidogenic phenotype’ in cancer cells. This in conjugation with ‘aerobic glycolysis (Warburg's effect)’ constitutes two major metabolic perturbations featured in cancer cells. Current understanding is that these mechanisms synergize to efficiently produce and utilize NADPH for the synthesis of macromolecules including lipids and nucleotides. This occurs while avoiding ROS-producing oxidative phosphorylation (OXPHOS) in mitochondria and preventing ATP production (Fig. 5). In addition, increased cellular cholesterol might suppress OXPHOS by altering the components of the mitochondria membrane. NADPH is also required for the synthesis of glutathione, an antioxidant. It is of note that wild-type p53 controls glycolysis in a bipolar manner, for example, by upregulating hexokinase 2, which promotes glycolysis, and TIGAR, which suppresses glycolysis. In total, inactivation of the p53 function is thought to result in the shift of cell metabolism to glycolytic (Fig. 5). Not only sequential regulation of SREBP expression and maturation, but also an astonishing level of cooperation in regulating cancer cell metabolism is becoming evident between pRB and p53 (Fig. 5). AMPKα2 was identified to be in a PI3K-sensitive gene group among E2F targets. This molecule functions as a subunit of a system that senses the cellular level of AMP and antagonizes many metabolic perturbations in cancer cells mostly driven by mTORC1, TSC2 or SREBP. Therefore, together with the phopshorylation of pRB by AMPK, these findings suggest a mutually suppressive genetic interaction between pRB and AMPK.[6, 7] AMPK also functions downstream of another tumor suppressor, LKB1. Metformin, an AMPK agonist, was suggested to lower the cancer risk in individuals who were administered the drug. Although E2F-AMPK genetic interaction was initially perceived in the context of apoptosis control, together with our knowledge on pRB genetic interaction with SREBP, Ras, AKT, Myc, p53, Oct-1 and HIF-1, this discovery will further our understanding of pRB functions in cancer cell metabolism.