Extracellular signal-regulated kinase 1/2 (Erk1/2) mitogen activated protein kinases (MAPKs) act within a conserved intracellular signaling pathway that canonically includes upstream Ras, Raf (MAP3K) and Mek (MAP2K) proteins. Prior AR49737 efforts demonstrated that Erk1/2 pathway signaling is integral to both epidermal homeostasis as well as to early tumor progression. We identified two Erk1/2-regulated long non-coding RNAs (lncRNAs) with essential roles in epidermal homeostasis, including, ANCR, which is required for epidermal progenitor tissue maintenance, and TINCR, which is required for epidermal differentiation. In searching for proteins that modulate Erk1/2 output, we targeted all Erk1/2 cascade-interacting proteins to identify IQGAP1 as the only MAPK scaffold that was dispensable for Erk1/2- mediated homeostasis but required for Erk1/2-driven tumor progression. This competing renewal will characterize how these Erk1/2 targets and interactors function. First, we will focus on new lncRNAs by defining their mechanistic actions in homeostatic maintenance. Anti-differentiation non-coding RNA (ANCR) is an Erk1/2-sustained, 855 bp lncRNA enriched in a variety of tissue progenitors that sustains the undifferentiated progenitor state. In contrast, terminal differentiation induced non-coding RNA (TINCR) is an Erk1/2- suppressed, differentiation-induced 3693 bp lncRNA containing 10 novel 25bp motifs that is required for epidermal differentiation. These two lncRNAs are each conserved and essential for epidermal homeostasis.
Aim I will test the hypotheses that defining ANCR's RNA, protein, and genomic interactome will yield insight into its mechanism of action and that TINCR acts within a larger RNA-protein complex to prevent degradation of differentiation mRNAs. Second, we will define IQGAP1-dependent Erk1/2 targets in Erk1/2 driven early tumor progression as a means of separating Erk1/2 homeostatic signaling from its tumorigenic actions. During the prior cycle, we identified IQGAP1 as the sole protein among the many Erk1/2 MAPK cascade scaffolds that is required for Erk1/2-mediated carcinogenesis yet is dispensable for tissue maintenance. IQGAP1 can itself interact with numerous other tumor- enabling proteins in addition to Erk1/2, however, including b-catenin, Akt and Cdc42.
Aim II will determine whether the Erk1/2 pathway is the dominant IQGAP1-interacting pathway in this setting and will characterize IQGAP1 targets in homeostasis and tumorigenesis. This proposal will define how the Erk1/2 MAPK pathway sustains homeostasis, yet also drives tumor progression, as a basis for new therapies for diseases of skin and other tissues.
Erk1/2 mitogen activated protein kinases (MAPKs) signal via an ancient pathway that plays an essential role in maintaining healthy body tissues, such as epidermis, but also in enabling tumors to develop. This proposal characterizes key Erk1/2 mediators of both processes.
|Jameson, Katherine L; Mazur, Pawel K; Zehnder, Ashley M et al. (2013) IQGAP1 scaffold-kinase interaction blockade selectively targets RAS-MAP kinase-driven tumors. Nat Med 19:626-30|
|Kretz, Markus; Siprashvili, Zurab; Chu, Ci et al. (2013) Control of somatic tissue differentiation by the long non-coding RNA TINCR. Nature 493:231-5|
|Kretz, Markus; Webster, Dan E; Flockhart, Ross J et al. (2012) Suppression of progenitor differentiation requires the long noncoding RNA ANCR. Genes Dev 26:338-43|
|Sen, George L; Boxer, Lisa D; Webster, Dan E et al. (2012) ZNF750 is a p63 target gene that induces KLF4 to drive terminal epidermal differentiation. Dev Cell 22:669-77|
|Bhaduri, Aparna; Qu, Kun; Lee, Carolyn S et al. (2012) Rapid identification of non-human sequences in high-throughput sequencing datasets. Bioinformatics 28:1174-5|
|Sen, George L; Reuter, Jason A; Webster, Daniel E et al. (2010) DNMT1 maintains progenitor function in self-renewing somatic tissue. Nature 463:563-7|
|Singh, Anurag; Greninger, Patricia; Rhodes, Daniel et al. (2009) A gene expression signature associated with "K-Ras addiction" reveals regulators of EMT and tumor cell survival. Cancer Cell 15:489-500|
|Scholl, Florence A; Dumesic, Phillip A; Barragan, Deborah I et al. (2009) Selective role for Mek1 but not Mek2 in the induction of epidermal neoplasia. Cancer Res 69:3772-8|
|Dumesic, Phillip A; Scholl, Florence A; Barragan, Deborah I et al. (2009) Erk1/2 MAP kinases are required for epidermal G2/M progression. J Cell Biol 185:409-22|
|Reuter, Jason A; Ortiz-Urda, Susana; Kretz, Markus et al. (2009) Modeling inducible human tissue neoplasia identifies an extracellular matrix interaction network involved in cancer progression. Cancer Cell 15:477-88|
Showing the most recent 10 out of 13 publications