Map2k4 Functions as a Tumor Suppressor in Lung Adenocarcinoma and Inhibits Tumor Cell Invasion by Decreasing Peroxisome Proliferator-Activated Receptor γ2 Expression

Abstract

MAP2K4 encodes a dual-specificity kinase (mitogen-activated protein kinase kinase 4, or MKK4) that is mutated in a variety of human malignancies, but the biochemical properties of the mutant kinases and their roles in tumorigenesis have not been fully elucidated. Here we showed that 8 out of 11 cancer-associated MAP2K4 mutations reduce MKK4 protein stability or impair its kinase activity. On the basis of findings from bioinformatic studies on human cancer cell lines with homozygous MAP2K4 loss, we posited that MKK4 functions as a tumor suppressor in lung adenocarcinomas that develop in mice owing to expression of mutant Kras and Tp53. Conditional Map2k4 inactivation in the bronchial epithelium of mice had no discernible effect alone but increased the multiplicity and accelerated the growth of incipient lung neoplasias induced by oncogenic Kras. MKK4 suppressed the invasion and metastasis of Kras-Tp53-mutant lung adenocarcinoma cells. MKK4 deficiency increased peroxisomal proliferator-activated receptor ␥2 (PPAR␥2) expression through noncanonical MKK4 substrates, and PPAR␥2 enhanced tumor cell invasion. We conclude that Map2k4 functions as a tumor suppressor in lung adenocarcinoma and inhibits tumor cell invasion by decreasing PPAR␥2 levels.

SAPK pathways and p53 cooperatively regulate PLK4 activity and centrosome integrity under stress

“…Therefore, the tumour-suppressive function of MKK4 is manifested particularly when p53 is also inactivated. Consistent with this notion, MKK4 mutations frequently coexist with p53 mutations in human cancer cells 48 . Given that PLK4 knockdown potentiated etoposide-induced apoptosis in p53-null cancer cells, PLK4 could be a potential therapeutic target for human cancer.…”

“…Together, these findings imply that, under stress conditions, the numeral integrity of centrosomes is preserved by SAPKs and p53, which might act synergistically. Because both p53 and the MKK4 SAPKK are frequently impaired in human cancers 48 , we next tested a hypothesis that was based on the current findings, namely that combined inhibition of MKK4 and p53 might evoke centrosome amplification in cells exposed to genotoxic stress. To inactivate MKK4, we utilized two cancer-derived dominant-negative MKK4 mutants (N234I and S251N), which inhibit SAPK activation 49 .…”

MAP2K4 (mitogen-activated protein kinase kinase 4)

“…These mutations are located primarily in the kinase domain. The mutations include frameshift, nonsense, and missense mutations and occur in colorectal, nonsmall-cell lung, melanoma, and ovarian cancer specimens (Ahn et al, 2011). The frequency of MKK4 homozygous deletions in high-grade ovarian serous carcinomas was reported to be 4,2%, which is similar to the rates observed in pancreatic (2%) and breast (4,5%) carcinomas (Nakayama et al, 2006).…”

“…These mutations are primarily located in the kinase domain of MAP2K4. The mutations include frameshift, nonsense, and missense mutations and have been reported to occur in colorectal, non-small-cell lung, melanoma, and ovarian cancer specimens (Ahn et al, 2011).…”

The 2 Faces of JNK Signaling in Cancer

“…36 Evidence that jnk1 +/− jnk2 −/− mice or mice with a specific loss of mkk4 or mkk7 gene expression in the bronchial epithelium developed Kras G12D -induced lung tumors earlier than their control littermates provided further support for a tumor-suppressive function of JNK downstream of oncogenic Ras. 37,38 Similarly, the loss of JNK1 or JNK2 enhanced mammary tumor development in mouse models of breast cancer driven by the decreased expression of p53 or ectopic expression of the polyoma middle T antigen transgene. [39][40][41] Consistently, conditional inactivation of M Monographs the mkk7 gene in mammary epithelial cells increased tumor formation induced by the NeuT oncogene.…”