Abstract
Oncogenes induce cell proliferation leading to replicative stress, DNA damage and genomic instability. A wide variety of cellular stresses activate c-Jun N-terminal kinase (JNK) proteins, but few studies have directly addressed the roles of JNK isoforms in tumor development. Herein, we show that jnk2 knockout mice expressing the Polyoma Middle T Antigen transgene developed mammary tumors earlier and experienced higher tumor multiplicity compared to jnk2 wildtype mice. Lack of jnk2 expression was associated with higher tumor aneuploidy and reduced DNA damage response, as marked by fewer pH2AX and 53BP1 nuclear foci. Comparative genomic hybridization further confirmed increased genomic instability in PyV MT/jnk2−/− tumors. In vitro, PyV MT/jnk2−/− cells underwent replicative stress and cell death as evidenced by lower BrdU incorporation, and sustained chromatin licensing and DNA replication factor 1 (CDT1) and p21Waf1 protein expression, and phosphorylation of Chk1 after serum stimulation, but this response was not associated with phosphorylation of p53 Ser15. Adenoviral overexpression of CDT1 led to similar differences between jnk2 wildtype and knockout cells. In normal mammary cells undergoing UV induced single stranded DNA breaks, JNK2 localized to RPA (Replication Protein A) coated strands indicating that JNK2 responds early to single stranded DNA damage and is critical for subsequent recruitment of DNA repair proteins. Together, these data support that JNK2 prevents replicative stress by coordinating cell cycle progression and DNA damage repair mechanisms.
Highlights
Numerous oncogenes including ErbB2, EGFR (Epidermal Growth Factor Receptor), and IGF-1R (Insulin-like Growth Factor 1 Receptor) have been therapeutically targeted in the past two decades
Jnk2 knockout shortens tumor latency and increases tumor multiplicity induced by the Polyoma Middle T Antigen (PyV MT) transgene
In the studies presented we set out to assess the contributions of JNK2 isoforms in mammary tumorigenesis and metastasis using the MMTV-PyV MT transgenic mouse model [18]
Summary
Numerous oncogenes including ErbB2, EGFR (Epidermal Growth Factor Receptor), and IGF-1R (Insulin-like Growth Factor 1 Receptor) have been therapeutically targeted in the past two decades. The tyrosine kinase receptors (TKRs) increase activity of the PI3K (Phosphatidylinositol 3-Kinase) and Ras/Shc/ MAPK pathways to enhance cell proliferation and suppress apoptosis. Oncogene induced replicative or oxidative stress can result in senescence as a barrier to tumor progression [1]. The Polyoma Middle T Antigen (PyV MT) oncogene activates PI3K and Shc/MAPK dependent pathways, and induces c-Jun phosphorylation (via JNK activation) and transcriptional activity [2]. The Met oncogene mediates transformation via PI3K and JNK [3]. These studies maintain that TKR induced JNK/c-Jun activity enhances tumorigenesis. No studies have addressed the specific functions of the various JNK proteins in TKR mediated cancer progression.
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