Cell division control protein A7 (CDCA7) is a recently identified target of MYC-dependent transcriptional regulation. We have discovered that CDCA7 associates with MYC and that this association is modulated in a phosphorylation-dependent manner. The prosurvival kinase AKT phosphorylates CDCA7 at threonine 163, promoting binding to 14-3-3, dissociation from MYC, and sequestration to the cytoplasm. Upon serum withdrawal, induction of CDCA7 expression in the presence of MYC sensitized cells to apoptosis, whereas CDCA7 knockdown reduced MYC-dependent apoptosis. The transformation of fibroblasts by MYC was reduced by coexpression of CDCA7, while the non-MYC-interacting protein ⌬(156 -187)-CDCA7 largely inhibited MYC-induced transformation. These studies provide insight into a new mechanism by which AKT signaling to CDCA7 could alter MYCdependent growth and transformation, contributing to tumorigenesis.
The transcription factor MYC is a proto-oncogene that regulates the expression of hundreds of genes involved in cell cycle progression, adhesion, metabolism, and apoptosis (1-4). Overexpression of MYC is a hallmark of human cancer, contributing to the expression of numerous groups of genes involved in transformation, metastasis, and overall poor prognosis (5, 6). MYC has been estimated to be active in nearly 70% of human cancers; the mechanisms of activation include amplification, translocation, deregulated translation, and protein turnover (7,8). As such, MYC has been the subject of extensive study in the search for treatment modalities (reviewed in references 3, 9, and 10).Activation of MYC is induced by mitogenic stimuli to promote cell cycle progression (11-17). To prevent aberrant MYC expression from driving unsafe proliferation in the animal, a safeguard has evolved whereby MYC activation in the absence of mitogenic survival signals is opposed by cellular responses of apoptosis and/or cell cycle arrest, depending on the cellular context and p53 status (18)(19)(20)(21)(22)(23)(24)(25). Despite these observations of almost 20 years ago and the realization that other growth-promoting transcription factors, such as E1A and E2F1, act similarly (26-29), the mechanism of MYC-induced apoptosis and cell cycle arrest is still poorly understood.Expression of prosurvival oncogenes, the earliest example of which is Bcl-2, has been shown previously to counteract the death function of MYC (30-32). Additionally, activation of phosphoinositide-3-kinase (PI3K) and its downstream target AKT can protect against apoptosis induced by MYC (33). PI3K and AKT were shown in the mid-1990s to convey a strong prosurvival signal downstream of receptor tyrosine kinases (34-36) by impacting the apoptosis machinery directly (37-40) and by regulating FOXO transcription factors (41-45). Furthermore, loss of the tumor suppressor MMAC1/PTEN results in constitutive PI3K signals (46, 47) and can lead to tumors in humans (48, 49). Thus, aberrant MYC activation together with overactive AKT, a condition that is often achieved in tumor cells, can provide ...
