Given the fact that numerous intra- and extra-cellular stimuli regulate the activation of Myc, it is expected that other unidentified kinases may be also involved. A cellular PP2A inhibitor cip2A which is overexpressed in several cancers has been shown to increase Myc levels via suppression of PP2A activity. Then, monophosphorylated Myc (at Thr58) is degraded by ubiquitin/proteosome system.
The Thr58/Ser62 dual phosphorylated Myc is acted on by protein phosphatase 2A to dephosphorylate Ser62. The Ser62 phosphorylated Myc is further phosphorylated at Thr58 by glycogen synthase kinase 3β. The kinases ERK (extracellular signal-regulated kinase), JNK (c-Jun N-terminal kinase) and cdk1 (cyclin-dependent kinase 1) have been identified to phosphorylate Myc at Ser62. Phosphorylation of Myc at Ser62 increases protein stability. The Myc protein level is further regulated by control of protein stability, which is determined by a complicated protein kinase/phosphatase system. Inhibition of these transcription factors suppresses cancer cell survival in part by decreasing Myc expression. Several transcription factors, including NF-κB, E 2F, STAT, and β-catenin, are involved in the regulation of Myc expression.
Abnormal expression of Myc is frequently associated with cancer progression. The oncogenic Myc protein is a transcription factor that regulates a wide spectrum of downstream genes involved in cancer cell metabolism, growth, and progression, and it is well documented that Myc plays an important role in breast cancer metastasis. The identification of new substrates of IKKs is important for the understanding of IKKs functions in cancer biology. The biological significance of IKKs is getting complicated and requires further characterization. For example, IKKα increases but IKKβ decreases the transcriptional activity and protein level of β-catenin. Interesting, IKKα and IKKβ may have opposite effect on certain proteins. For example, IKKβ phosphorylates tumor suppressor FOXO3a, and consequently induces FOXO3a nuclear exclusion and degradation, thereby promoting tumor survival.
However, accumulating evidence has indicated that IKKs have NF-κB- independent effects on multiple proteins. Most studies regarding IKKs are actually focused on their downstream molecule, NF-κB, and the thinking that IKKs might be therapeutic targets is trying to indirectly suppress NF-κB activation. Numerous reports have indicated that the functions of IKKs are necessary for cancer cell survival and progression. The released NF-κB translocates into the nucleus and then regulates the expression of multiple genes. The complex functions as an upstream kinase involved in the activation of nuclear factor kappa B(NF-κB)by phosphorylation of the NF-κB inhibitory molecule, IκBα, resulting in the subsequent degradation of IκBα through the ubiqutin/proteasome pathway. The IKK complex is composed of two kinase catalytic subunits IKKα and IKKβ and a non-kinase scaffold protein IKKγ. Our study indicates that IKKs tightly regulate Myc expression through prolonging protein stability, and suggests that IKKs are potentially therapeutic targets and that suppression of IKKs may be used following chemotherapy to reduce the risk of treatment-induced tumor progression. Inhibition of IKKs prevents these doxorubicin-induced effects. Furthermore, doxorubicin, a frequently used anticancer drug in breast cancer, activates IKKs and Myc, thereby increasing invasiveness and tumorigenesis of breast carcinoma MCF7 cells. Consequently, these treatments decrease the tumorigenic and invasive ability of breast cancer cells. Suppression of IKK activity by either chemical inhibitor or transfection of kinase-dead mutants decreases the phosphorylation of Myc at Ser62 and enhances the degradation of Myc. In this study, we show that the expression of Myc is associated with IKKα and IKKβ in breast cancers and that Myc is an IKKs substrate. The levels of Myc is regulated by the phosphorylation of Myc at Thr58 and Ser62. Both IκB kinase (IKK) complex and oncgenic protein Myc play important roles in cancer progression, including cancer cell invasiveness and metastasis.
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