Biallelic mutation of SOCS-1 impairs JAK2 degradation and sustains phospho-JAK2 action in the MedB-1 mediastinal lymphoma line.
Primary mediastinal B-cell lymphoma (PMBL) is a well-defined subtype of diffuse large B-cell lymphoma. Molecular cytogenetics revealed frequent gains of 9p24. JAK2, mapping in this region, is presently regarded as a candidate oncogene because expression profiling showed high Janus kinase-2 (JAK2) transcript levels and JAK2 was found to be constitutively phosphorylated in mediastinal B-cell lymphomas. We confirm that in the MedB-1 mediastinal B-cell line, harboring a trisomy 9, JAK2 transcription is elevated and the product is highly phosphorylated. However, JAK2 is not overexpressed at the protein level. On top, JAK2 protein turnover is even delayed. This unexpected finding coincides with a biallelic mutation of the suppressor of cytokine signaling-1 (SOCS-1) gene in this cell, which abrogates SOCS box function of the protein. Ectopic expression of wild-type (wt) SOCS-1 in MedB-1 leads to growth arrest and dramatic reduction of phospho-JAK2 and its downstream partner phospho-signal transducer and activator of transcription-5 (phospho-STAT5). Ultimately, the target gene cyclin D1 is repressed in transfectants while RB1, which is silenced in MedB-1, is induced. We conclude that, in MedB-1, action of phospho-JAK2 is sustained due to defective SOCS-1. Hence, SOCS-1 qualifies as a novel tumor suppressor. Of note, SOCS-1 mutations are also present in the parental tumor of MedB-1 and were detected in 9 of 20 PMBLs.
Melzner
Ingo
I
Department of Pathology, University of Ulm, Albert-Einstein-Allee 11, D-89081 Ulm, Germany.
Bucur
Alexandra Juliana
AJ
Brüderlein
Silke
S
Dorsch
Karola
K
Hasel
Cornelia
C
Barth
Thomas F E
TF
Leithäuser
Frank
F
Möller
Peter
P
D000483:Alleles; D045744:Cell Line, Tumor; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D053614:Janus Kinase 2; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism*; D008479:Mediastinal Neoplasms / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics* / Q000378:metabolism; D014314:Trisomy / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; C108944:SOCS1 protein, human; D050799:STAT5 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2