Experimental MethodsI have successfully established two novel mouse models of MTC. One model utilizes the CGRPCreER mouse line, where inducible Cre recombinase from CGRPCreER was used for the selective inactivation of the tumor suppressors Rb and PHLDA3 in C cells. I named this model the ‘ CRb mouse model’. The second model involves Rb heterozygous mice with varying PHLDA3 genotypes, which I named the ‘ Rb+/- mouse model’.Results and Discussion1)PHLDA3 is a Repressor of AKT Oncoproteinp53, known as the “guardian of the genome,” responds to cellular stresses like DNA damage, low oxygen, and oncogene activation by becoming activated through phosphorylation and acetylation 7). Once activated, it stabilizes and moves to the nucleus, where it functions as a transcription factor that regulates genes involved in processes like apoptosis, cell cycle arrest, autophagy, and senescence to prevent tumor development 8). One of its direct target genes is PHLDA3, as confirmed by computational predictions and validated by experimental methods such as ChIP-chip, ChIP-seq, and Global Run-On sequencing 2). PHLDA3 encodes a 127-amino acid protein with a pleckstrin homology (PH) domain that enables it to bind phosphatidylinositol phosphates (PIPs) and localize to the cell membrane. It functions as a dominant-negative inhibitor of the oncogenic AKT pathway by competing with AKT for binding to PIP3 on the membrane. Since AKT activation relies on PIP3 binding and subsequent phosphorylation, PHLDA3 disrupts this process, thereby suppressing AKT’s downstream pro-survival and proliferative signaling. This positions PHLDA3 as a key negative regulator of AKT and the PI3K/AKT signaling pathway (Fig. 2) 9).Fig 2. Role of PHLDA3 in the PI3K/AKT signaling pathway.2)PHLDA3 in PanNETs Prior research has established a connection between Loss of heterozygosity (LOH) at the 1q31 ― 240 ―A) A schematic diagram of PHLDA3. Pleckstrin Homology (PH). B) Growth factor stimulation activates PI3K, which converts PIP2 into PIP3, facilitating AKT recruitment to the cell membrane via its PH domain.
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