Dual regulation of Myc by Abl

Abstract

The Tyrosine kinase c-Abl (or Abl) and the prolyl-isomerase Pin1 cooperatively activate the transcription factor p73 by enhancing recruitment of the acetyl-transferase p300. Since the transcription factor c-Myc (or Myc) is a known target of Pin1 and p300, we hypothesized that it might be regulated in a similar manner. Consistent with this hypothesis, over-expression of Pin1 augmented Myc's interaction with p300 and transcriptional activity. The action of Abl, however, was more complex than predicted. On one hand, Abl indirectly enhanced phosphorylation of Myc on Ser 62 and Thr 58, its association with Pin1 and p300, and its acetylation by p300. These effects of Abl were exerted through phosphorylation of substrate(s) other than Myc itself. On the other hand, Abl interacted with the C-terminal domain of Myc and phosphorylated up to five Tyrosine residues in its N-terminus, the principal of which was Y74. Indirect immunofluorescence or immuno-histochemical staining suggested that the Y74-phosphorylated form of Myc (Myc-pY74) localized to the cytoplasm and co-existed either with active Abl in a subset of mammary carcinomas, or with Bcr-Abl in Chronic Myeloid Leukemia. In all instances, Myc-pY74 constituted a minor fraction of the cellular Myc protein. Thus, our data unravel two potential effects of Abl on Myc: first, Abl signaling can indirectly augment acetylation of Myc by p300, and most likely also its transcriptional activity in the nucleus; second, Abl can directly phosphorylate Myc on Tyrosine: the resulting form of Myc appears to be cytoplasmic, and its presence correlates with Abl activation in cancer.

Pin1 Regulates the Dynamics of c-Myc DNA Binding To Facilitate Target Gene Regulation and Oncogenesis

“…Our work suggests that Pin1 functions as a unique Myc coactivator, controlling the dynamics of Myc DNA binding, as well as facilitating Myc's recruitment of p300, GCN5, hSNF5, and pTEFb to promoters. In agreement with our data, Sanchez-Arevalo Lobo et al have recently shown that Pin1 augments Myc's interaction with p300 to increase transcriptional activity (66). At this point, it is unclear whether Pin1's facilitation of Myc's association with transcriptional coactivators controls its dynamic interaction with DNA through their chromatin-remodeling activity or if Pin1-mediated isomerization of Myc facilitates its DNA interaction and this then helps stabilize its interaction with the other coactivators.…”

FBXO32 Targets c-Myc for Proteasomal Degradation and Inhibits c-Myc Activity

“…2, A and B, co-expression of HA-FBXO32 promotes degradation in all of these mutants. In addition to these three sites, four other sites (Ser-71, Tyr-74, Thr-358, and Ser-373) in c-Myc have also been reported to be phosphorylation sites (33)(34)(35)(36). We found that HA-FBXO32 also promotes degradation in all four mutants (S71A, Y74A, T358A, and S373A) (Fig.…”

MYC Degradation

“…Similar changes in MYC phosphorylation and MYC protein stability are seen in pancreatic cancer (AS Farrell et al, in prep.). Importantly, in conjunction with the high Pin1 observed in many cancers (Ayala et al 2003;Lu 2003;Miyashita et al 2003;Ryo et al 2003;Wulf et al 2003;Lam et al 2008), this pS62-MYC present in cancer cells is expected to be highly transcriptionally active (Farrell et al 2013;Sanchez-Arevalo Lobo et al 2013). Studies exploring signaling mechanisms that could contribute to this altered MYC phosphorylation and stabilization have observed, in addition to the common activation of MEK/ERK signaling, decreased expression of PP2A-B56a and altered Axin1 splicing in some cancer cell lines that express S62-phosphorylated and stabilized MYC (Mannava et al 2012;Zhang et al 2012;RC Sears, unpubl.).…”

“…Recent data suggest that Pin1 functions at two points in the above pS62/pT58 MYC degradation pathway, where it first catalyzes proline 63 in pS62-MYC from trans to cis to enhance its DNA binding and transcriptional activity, and subsequently catalyzes proline 63 in pS62/pT58-MYC from cis to trans to facilitate PP2A-mediated dephosphorylation of S62, and in this way contributes to pT58-MYC degradation via the Fbw7 E3 ligase (Farrell et al 2013;Sanchez-Arevalo Lobo et al 2013). These studies support a coupled relationship between MYC's transcriptional activity and its degradation (see discussion below).…”