The Molecular Mechanisms Of C-Abl Tyrosine Kinase Involving In The Regulation Of Gene Transcription

The c-Abl proto-oncogene encodes a ubiquitously expressed 145kDanon-receptor tyrosine kinase, which is predominantly localized to nucleus. Thefunction of c-Abl is required for the normal growth and development because c-Abldeficient mice exhibited the phenotype of embryonic or neonatal lethality. c-Abl hasbeen implicated in a wide variety of cellular processes, including the regulation of cellgrowth and survival, oxidative stress and DNA damage responses, actin dynamics,signal transduction, and gene transcription. Although it has been known that c-Ablparticipate in the regulation of gene transcription, the molecular mechanisms of c-Ablregulating gene transcription remain in large elusive, and the knowledge of genetranscription regulated by c-Abl needs to be expanded. In this study, we showed that c-Abl promoted the transcription of c-fos gene,both exogenously and endogenously. The nuclear localization and tyrosine kinaseactivity of c-Abl were requried for the activation of c-fos gene. c-Abl was associatedwith RNA polymerase II (RNAP II) in vivo and augumented the tyrosinephosphorylation of the largest subunit of RNAP II. In addition, c-Abl and RNAP IIcould be recruited to the region of c-fos promoter. Expression of CTD of the largestsubunit of RNAP II inhibits the activation of c-fos promoter by c-Abl. It has beensuggested that phosphorylation of the largest subunit of RNAP II by c-Abl involves intranscription initiation as well as elongation. Our results suggest that c-Abl plays animportant role in the regulation of c-fos gene transcription and the tyrosinephosphorylation of the largest subunit of RNAP II by c-Abl is involved in theregulating process. We also showed that c-Abl tyrosine kinase exogenously activated thetranscription of p21 promoter and correspondingly endogenously increased the yieldof p21 mRNA. c-Abl can be recruited to the p53 binding region of p21 promoter. p53is involved in the activation of p21 promoter by c-Abl. By conducting dual-luciferaseassay by cotransfecting K562 cells (p53-deficient cells) with c-Abl, STAT5 expressionplasmids and p21-luc report, we showed that c-Abl might promote the transcription ofp21 gene via activating STAT5, independent on p53. Results presented in this paper has proved that c-Abl tyrosine kinase involved inregulating gene transcription and these original results will be helpful forunderstanding the molecular mechanism of c-Abl regulating gene transcripition.