Apoptosis is controlled by several genes. Among the most crucial regulators of this process are members of the Bcl-2 gene family. Bcl-2 is an anti-apoptotic gene which has the ability to block a wide variety of apoptotic signals, and its expression has been reported in a large number of human neoplasms, including breast, prostate and thyroid carcinoma and large cell carcinoma of the lung.

Bax is another member of the Bcl-2 family, but in contrast to Bcl-2 it has an apoptosis-stimulating function. Gene products of the Bcl-2 family can form homo- and heterodimers with each other. The pro-apoptotic action of Bax protein is dependent on the formation of Bax homodimers on the outer mitochondrial membrane. One factor which appears to ragulate the formation of theses homodimers appears to be vitamin A in the form of all-transretinoic acid as well as to some degree retinyl acetate.

The antagonistic effects of Bcl-2 protein have been at least partially accounted for by its ability to form Bcl- 2-Bax heterodimers, thus preventing the formation of Bax homodimers. Hence, it has been proposed that the cellular Bcl-2/Bax ratio is a key factor in the regulation of apoptosis; a high Bcl-2/Bax ratio makes cells

resistant to apoptotic stimuli, while a low ratio induces cell death.

Tumor necrosis factor (TNF)-alpha is a cytokine that can induce apoptosis through its specific receptors. Activation of TNF receptors leads to subsequent activation of proteolytic enzymes (caspases) that are responsible for the execution of apoptosis.

The members of the tumour necrosis factor ligand family (TNFs) may induce both apoptotic and anti-apoptotic pathways. TNFs transduces cellular responses through activation of different TNF-receptors (TNFRs).

One important mechanism of cell survival is the activation of transcription of different anti-apoptotic proteins by TNFs via the nuclear factors of kappa light polypeptide in B-cells ( NF-kB ) signaling cascade.

TNF-alpha upregulates release of Bcl-2 through the TNF-R1 reseptor with the subsequent release of TRADD->RIPK1->IKK-gamma-> NFkB-> Bcl-2

Subsequent effect of Bcl-2 then depends on formation of heterodimers, which in turn is regulated by IL-6, SOD, COX, NO, p52, p50 and a long list of variable cytokines.

TGF alpha and TNF alpha are released into circulation by adam17, a Disintegrin metalloproteinase. ADAM17 overexpression is correlated with cancer. There are compounds that inhibit adam17 and were in the clinic for treating cancer. TGF alpha and other EGF family members are major promoters of cancer. ADAM family members process the EGF and EGFR family members. Inhibition of processing events is a major way to treat cancer, and also improve,efficacy of existing drugs such as Herceptin and the EGFR neutralizing antibodies. BCL2 is related to apoptosis. ADAM17 inhibitors may cause APOPtosis of cancer cells. ADAMs also get cleaved themselvesf. All of these membrane proteins, when cleaved leave behind a c- terminal fragment that regulates gene transcription. So things get quite complicated. But the link between TGF alpha, and TNF, and other cytokines is that the are all either processed by ADAM family members, and/or regulated by ADAM family members at the transcriptional level.

VitaminA up regulates ADAM10 activity which would probably decrease TGF alpha levels and decrease TNf levels in cancer cells.