PRAK suppresses oncogenic ras-induced hematopoietic cancer development by antagonizing the JNK pathway.
The p38 mitogen-activated protein kinase (MAPK) pathway regulates multiple physiologic and pathologic processes, including cancer development. PRAK, a p38 substrate protein kinase, has previously been implicated in the suppression of skin carcinogenesis. In the current study, we show that PRAK deletion accelerates hematopoietic cancer development in a mouse model harboring an oncogenic ras allele, Eμ-N-Ras(G12D), specifically expressed in hematopoietic cells. Further investigation reveals that enhanced hematopoietic tumorigenesis by PRAK deficiency is associated with hyperactivation of the c-jun-NH(2)-kinase (JNK) pathway both in vivo and in primary hematopoietic cells isolated from spleens. In primary splenocytes, PRAK deficiency further enhanced oncogenic ras-induced cell proliferation and promoted ras-mediated colony formation on semisolid medium in a JNK-dependent manner. In addition, deletion of PRAK leads to abrogation of ras-induced accumulation of senescence markers. These findings indicate that PRAK suppresses hematopoietic cancer formation in this mouse model by antagonizing oncogenic ras-induced activation of the JNK pathway. Our results suggest that PRAK may function as a tumor suppressor in multiple types of cancers.
Department of Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, CA 92037, USA.
Naoto
N
Yoshizuka
Maoyi
M
Lai
Rong
R
Liao
Ryan
R
Cook
Changchun
C
Xiao
Jiahuai
J
Han
Peiqing
P
Sun
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D019337:Hematologic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D016130:Immunophenotyping; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; C111049:MAP-kinase-activated kinase 5; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D018631:ras Proteins