Differential regulation of SOCS genes in normal and transformed erythroid cells.
The SOCS family of genes are negative regulators of cytokine signalling with SOCS-1 displaying tumor suppressor activity. SOCS-1, CIS and SOCS-3 have been implicated in the regulation of red blood cell production. In this study, a detailed examination was conducted on the expression patterns of these three SOCS family members in normal erythroid progenitors and a panel of erythroleukemic cell lines. Unexpectedly, differences in SOCS gene expression were observed during maturation of normal red cell progenitors, viz changes to CIS were inversely related to the alterations of SOCS-1 and SOCS-3. Similarly, these SOCS genes were differentially expressed in transformed erythoid cells - erythroleukemic cells immortalized at an immature stage of differentiation expressed SOCS-1 and SOCS-3 mRNA constitutively, whereas in more mature cell lines SOCS-1 and CIS were induced only after exposure to erythropoietin (Epo). Significantly, when ectopic expression of the tyrosine kinase Lyn was used to promote differentiation of immature cell lines, constitutive expression of SOCS-1 and SOCS-3 was completely suppressed. Modulation of intracellular signalling via mutated Epo receptors in mature erythroleukemic lines also highlighted different responses by the three SOCS family members. Close scrutiny of SOCS-1 revealed that, despite large increases in mRNA levels, the activity of the promoter did not alter after erythropoietin stimulation; in addition, erythroid cells from SOCS-1-/- mice displayed increased sensitivity to Epo. These observations indicate complex, stage-specific regulation of SOCS genes during normal erythroid maturation and in erythroleukemic cells.
Sarna
Mohinder K
MK
Laboratory for Cancer Medicine, Western Australian Institute for Medical Research, Royal Perth Hospital and Centre for Medical Research, The University of Western Australia, Perth, Australia.
Ingley
Evan
E
Busfield
Samantha J
SJ
Cull
Vanessa S
VS
Lepere
Winald
W
McCarthy
David J
DJ
Wright
Michael J
MJ
Palmer
Gene A
GA
Chappell
David
D
Sayer
Melissa S
MS
Alexander
Warren S
WS
Hilton
Douglas J
DJ
Starr
Robyn
R
Watowich
Stephanie S
SS
Bittorf
Thomas
T
Klinken
S Peter
SP
Tilbrook
Peta A
PA
D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D002454:Cell Differentiation; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004921:Erythropoietin / Q000494:pharmacology; D005786:Gene Expression Regulation; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D009154:Mutation; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D017467:Receptors, Erythropoietin / Q000235:genetics; D012097:Repressor Proteins; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D015533:Transcriptional Activation; D019061:src-Family Kinases / Q000378:metabolism
D002352:Carrier Proteins; D004921:Erythropoietin; D017874:Immediate-Early Proteins; D011506:Proteins; D012333:RNA, Messenger; D017467:Receptors, Erythropoietin; D012097:Repressor Proteins; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D019061:src-Family Kinases; C491590:Socs1 protein, mouse; C491411:Socs3 protein, mouse; C060902:lyn protein-tyrosine kinase