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Cyclin D1 gene expression regulation mechanism of

Author: GuoZhiYi
Tutor: Shen;WuNingHua;ZhangYe
School: Peking Union Medical College , China
Course: Biochemistry and Molecular Biology
Keywords: Cyclin Gene promoter Heat shock Promoter activity Response element Reporter gene Medical Point mutation Co-transfected Regulatory mechanism
Type: PhD thesis
Year: 2006
Downloads: 160
Quote: 0
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Cyclin D1, a key regulator in G1 phase of cell cycle, can form complex with CDK4/6and the complex phosphorylates Rb protein to initiate cell cycle progression towards Sphase. Cyclin D1 can be regulated at protein level such as its degradation by ubiquitinaton.The regulation also occurs at the transcription level. This study focuses on its transcriptionregulation mechanism under heat shock.1. NF-γB site, -39/-30 region of the Cyclin D1 gene promoter, is responded for thedepression of cyclin D1 gene promoter activityWhen treated with heat shock, the decrease of cyclin D1 mRNA was detected byRT-PCR analysis. To investigate whether heat shock treatment results in down-regulationof cyclin D1 through regulating its transcription, the plasmids of CAT reporter gene drivenby "full-length", truncation and mutant of cyclin D1 promoter are constructed. A549 cellswere transfected with all these reporter plasmids respectively together with the internalcontrol plasmid of pM-CAT, data showed that the heat response disappears when the theNF-κB site mutated2. ChIP (Chromatin Immunoprecipitation) analysis show that the binding of mSin3A onthe NF-κB site(-39/-30) of the Cyclin D1 gene promoter increased after heat shocktreatment.Antibodies against p65 (the subunit of NF-κB), mSin3A, p53, Ac-H3-k9(acetylatedHistone3 at lysine 9), P300, PCAF and BRM were used in ChIP. The results showed thatthe binding of P65 on that region had no change, while mSin3A and P53 binding increasedafter heat shock. The binding activity of Ac-H3-k9 decrease and P300 PCAF binding dosenot show significant change. The binding activity of Brm, the ATPase subunit of SWI/SNFcomplex, had no significant change. The results suggest that during heat shock treatmentHDACs is recruited to the NF-rd3 site(-39/-30) of the Cyclin D1 gene promoter whichresults in transcription depression. 3. co-transfection and reporter gene analysis show that HDAC bind to P65 under heatshock, and P53 can facilities this process.The reporter plasmids were co-transfected with the expression plasmid of P65, HDAC1,and HDAC2, respectively. Data show that HDAC1 and HDAC2 can repress the promoteractivity. Repression of the cyclin D1 promoter under heat shock is not influenced byco-transfected with P65 expression plasmid, whereas TSA, a HDAC inhibitor, can abolishthe effect. P53 repressed the cyclin D1 promoter activity and is NF-κB site dependent in-50~+141 region. So we can deduce that HDACs repress the promoter activity of CyclinD1 gene with heat shock treatment, and perhaps when heat treatment, HDACs replacedsome activators which bind to P65 before heat shock treatment. BRM activate the cyclinD1 gene promoter while depress it under heat shock which show the NF-κB site(-39/-30)of the Cyclin D1 gene promoter dependent. So MRM participate in this process anddepress the Cyclin D1 gene promoter activity through recruitting HDACs.In conclusion, the decrease of cyclin D1 promoter activity under heat shock is the-39NF-κB cis-element dependent. In this process, HDACs can increase association at this siteto repress the promoter activity. This is new a found beyond HSE/HSF regulation pathwayin gene expression regulation with heat shock.

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CLC: > Biological Sciences > Genetics
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