Figure 3.

MYC proteins and SKP2. SKP2 is an oncoprotein which can be upregulated by MYC proteins to drive tumorigenesis. SKP2 is a direct target gene of c-MYC, and can regulate the stability of c-MYC and be a co-factor for c-MYC mediated transcriptional activation of target genes. Due to the homology between c-MYC and MYCN, it is possible that SKP2 is also a direct target gene of MYCN and plays a similar role in regulating MYCN stability and transactivation of MYCN target genes (as indicated by the dashed lines). In neuroblastoma, MYCN can indirectly upregulate SKP2 via CDK4. In addition to upregulation by oncogenic MYC proteins, several signaling pathways closely linked to carcinogenesis such as PI3K/AKT and mTOR have been shown to influence SKP2 expression, stability and SCF^SKP2 ligase activity. SKP2 is a component of the SCF^SKP2 complex which mediates the degradation of several substrates including CDK inhibitors p21^CIP1, p27^KIP1, and p57^KIP2. Independently of SCF complex formation, SKP2 can bind to p300 and attenuate p53 function. Interestingly, p300 is able to reciprocally regulate SKP2 activity. SKP2B, an alternatively spliced variant of SKP2, can perturb both p53 and pRB pathways via degradation of Prohibitin. It is possible that SKP2 has other functions which may promote tumorigenesis.