ZFP36L1 negatively regulates erythroid differentiation of CD34+ hematopoietic stem cells by interfering with the Stat5b pathway.
ZFP36L1 is a member of a family of CCCH tandem zinc finger proteins (TTP family) able to bind to AU-rich elements in the 3'-untranslated region of mRNAs, thereby triggering their degradation. The present study suggests that such mechanism is used during hematopoiesis to regulate differentiation by posttranscriptionally modulating the expression of specific target genes. In particular, it demonstrates that ZFP36L1 negatively regulates erythroid differentiation by directly binding the 3' untranslated region of Stat5b encoding mRNA. Stat5b down-regulation obtained by ZFP36L1 overexpression results, in human hematopoietic progenitors, in a drastic decrease of erythroid colonies formation. These observations have been confirmed by silencing experiments targeting Stat5b and by treating hematopoietic stem/progenitor cells with drugs able to induce ZFP36L1 expression. Moreover, this study shows that different members of ZFP36L1 family act redundantly, because cooverexpression of ZFP36L1 and family member ZFP36 determines a cumulative effect on Stat5b down-regulation. This work describes a mechanism underlying ZFP36L1 capability to regulate hematopoietic differentiation and suggests a new target for the therapy of hematopoietic diseases involving Stat5b/JAK2 pathway, such as chronic myeloproliferative disorders.
Vignudelli
Tatiana
T
Università di Modena e Reggio Emilia, Dipartimento di Scienze Biomediche, Sezione di Chimica Biologica, 41100, Modena, Italy.
Selmi
Tommaso
T
Martello
Andrea
A
Parenti
Sandra
S
Grande
Alexis
A
Gemelli
Claudia
C
Zanocco-Marani
Tommaso
T
Ferrari
Sergio
S
D020413:3' Untranslated Regions / Q000235:genetics; D018952:Antigens, CD34 / Q000378:metabolism*; D015415:Biomarkers; D051817:Butyrate Response Factor 1 / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002935:Cinnamomum zeylanicum / Q000737:chemistry; D015536:Down-Regulation / Q000187:drug effects; D041905:Erythroid Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005312:Fetal Blood / Q000166:cytology; D005419:Flavonoids / Q000494:pharmacology; D020868:Gene Silencing / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology; D010936:Plant Extracts / Q000494:pharmacology; D059808:Polyphenols; D011485:Protein Binding / Q000187:drug effects; D020871:RNA Stability / Q000187:drug effects; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051816:Tristetraprolin / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D000099185:Interferon Regulatory Factor-8
D020413:3' Untranslated Regions; D018952:Antigens, CD34; D015415:Biomarkers; D051817:Butyrate Response Factor 1; D005419:Flavonoids; D050835:Interferon Regulatory Factors; D010636:Phenols; D010936:Plant Extracts; D059808:Polyphenols; D050799:STAT5 Transcription Factor; D051816:Tristetraprolin; D000099185:Interferon Regulatory Factor-8; C494095:STAT5B protein, human; C497552:ZFP36 protein, human; C102034:ZFP36L1 protein, human