Abstract
It has previously been shown that deregulated cโmyc blocks terminal myeloid differentiation and prematurely recruits both the Type I and II CD95/Fas apoptotic pathways, promoting an incompletely penetrant apoptotic response. In this work it is shown that deregulated expression of either mycER or mycERโข variants also blocked terminal myeloid differentiation but failed to induce the apoptotic response, demonstrating that cโmyc can block differentiation independent of the apoptotic response. The failure of the mycERโข transgene to cause the apoptotic response is associated with reduced levels of RIP1 expression, increased Mclโ1 expression and activation of both NFโkB and Akt. In addition, deregulating expression of RIP1 in M1mycERโข cells restored the apoptotic response. Thus altering cโMyc or its downstream effectors can influence the balance between apoptosis and survival, and ultimately the oncogenic potential of the cโmyc oncogene. This knowledge can be exploited to manipulate the downstream effectors, such as RIP1, to promote apoptosis and drive the death of cancer cells. J. Cell. Physiol. 216: 120โ127, 2008. ยฉ 2008 WileyโLiss, Inc.