TGFβ and tumor suppression. (a) Cell cycle inhibition. TGFβ exerts strong cytostatic effects and induces cell cycle arrest in the G1 phase by increasing the expression of the small cyclin-dependent kinase inhibitors p15, p21, and p27. These effects are Smad-dependent but also require the transcription factors Sp1 and FoxO. p15 directly inhibits CDK4/6 and displaces p21 and p27 from their preexisting CDK4/6 complexes allowing them to bind and inhibit CDK2-cyclin A/E complexes (orange arrows). TGFβ-induced cell cycle arrest also relies on the downregulation of the oncogene c-myc through Smads and repressor E2F4/5. The transcription factors from the ID family are also repressed by TGFβ through Smads, MAD2/4, and ATF3, further contributing to TGFβ-mediated cell cycle arrest. Finally, other pathways, potentially more tissue specific, have been described, including upregulation of the tumor suppressor menin in pituitary adenomas, leading to G1 arrest, and downregulation of the tyrosine phosphatase CDC25A in mammary epithelial cells, also leading to G1 arrest. (b) Induction of apoptosis. A central pathway in the mediation of the TGFβ proapoptotic effects involves the E2F1-pRb-P/CAF pathway that leads to gene transcription of multiple TGFβ proapoptotic target genes in various types of normal and cancer cells. In hematopoietic cells, TGFβ specifically induces expression of the lipid phosphatase SHIP, which in turn decreases second messenger PIP3 level and blocks Akt-mediated survival pathways, leading to cell death in both B and T lymphocytes. Other tissue specific proapoptotic pathways have been described downstream of TGFβ, including the TGFβ-mediated induction of the two proapoptotic proteins DAXX and DAPK in liver cells, the transcription factor TIEG1 in pancreatic cells, and the mitochondrial protein ARTS. TGFβ also promotes apoptosis in an SAPK-dependent manner by inducing pro-apoptotic target gene expression (Bmf, Bim and Bax) and by repressing antiapoptotic gene expression (Bcl-Xl and Bcl-2), further inducing mitochondrial release of cytochrome C and activation of the apoptosome, leading to caspase-dependent apoptosis in hepatocytes and B-lymphocytes. In colon cancer, TGFβ was also shown to inhibit expression of the prosurvival protein survivin. (c) Inhibition of cell immortalization. TGFβ also exerts its tumor suppressive effects through inhibition of cell immortalization in normal and cancer cells. This effect is mediated through the Smad, p38, and JNK pathways and requires recruitment of histone deacetylases (HDAC) to the telomerase (hTERT) gene promoter, further leading to inhibition of telomerase expression, and thereby preventing cell immortalization.