Molecular mechanisms of IL-6 protection againstp53 mediated apoptosis in myeloid leukemic cells

Regulation of myeloid cell homeostasis provides an excellent model to study molecular processes that govern survival, proliferation, differentiation and apoptosis of mammalian cells, and how aberrations in these processes can result in oncogenesis. In this research, M1 myeloid leukemic cells were used to dissect molecular mechanisms that contribute to the regulation of myeloid cell survival and apoptosis. A salient feature of M1 cells is that they respond to the physiological survival factor IL-6, yet lack the tumor suppressor gene p53, which is known to be mutated in more than half of all human cancers, and is a critical determinant of the cellular decision to either arrest growth and allow for repair of DNA damage, or to undergo apoptosis. Functional wild type activation of a temperature sensitive p53 protein (p53 val) at the permissive temperature in M1-t-p53 cells results in rapid apoptosis, which is blocked by IL-6. How p53 induces M1 apoptosis and how IL-6 protects against p53-induced apoptosis are not fully understood. It is shown that p53--mediated apoptosis of M1 cells involves rapid activation of the pro-apoptotic Fas/CD95 death pathway, including the Type I and Type II pathways, which result in caspase 8, 9, and 10 activation. p53 activation also resulted in upregulation of pro-apoptotic Bax and downregulation of pro-survival Bcl-2. IL-6 was found to protect against p53-induced apoptosis via activation of the P13K/Akt survival pathway, which in turn counters the Fas/CD95 pathway. Moreover, IL-6 mediated P13K/Akt pro-survival signaling was found to counter p53-mediated apoptosis by facilitating the expression of pro-survival bcl-2-like protein Mcl-1, and by activating the pro-survival transcription factor, NFkappaBeta. Taken together, this work supports a model for leukemic progression where cells that acquire the ability to produce an autocrine survival factor, such as 1L-6, can bypass normal p53 surveillance function by targeting Akt, which in turn can exert effects on regulators of apoptosis, such as the Fas/CD95 pathway, the mitochondria, and NFkappaBeta.