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"This thesis presents the first report of the comprehensive and quantitative analysis of the effects of tumor-derived mutations on the tetrameric structure of tumor suppressor protein p53, which plays a central role in maintaining genomic integrity. Inactivation of p53 via mutation of its gene is a key step in tumorigenesis. Biophysical analyses revealed that the stability of the mutant peptides varied widely. Formation of a tetrameric structure is to be critical for protein–protein interactions, DNA binding, and the post-translational modification of p53. A small destabilization of the tetrameric structure therefore could result in dysfunction of tumor suppressor activity. This work suggests that the threshold for loss of tumor suppressor activity, in terms of the disruption of p53’s tetrameric structure, could be extremely low. Furthermore, functional control of p53 via tetramer formation was demonstrated, based on the structure–function analysis of mutant p53. The results disclosed that relatively small changes in tetramer formation, induced by the stabilization or inhibition of homo-tetramerization, could control p53 function."

"Glioblastoma multiforme (GBM) merupakan tipe kanker yang agresif dan malignan dengan persentase kejadian tertinggi untuk tumor malignan primer pada sistem saraf pusat. Pengobatan standar pasien GBM yang salah satunya menggunakan kemoterapi temozolomide (TMZ) masih belum optimal dikarenakan dapat memicu resistensi GBM terhadap terapi. Studi terdahulu memperlihatkan adanya pengaruh senesens terhadap pembentukan kemoresistensi dan regulasi immunosurveillance (pengawasan imun) antikanker sel NK dan sel T sitotoksik, salah satunya melalui MICA/B. Namun, kaitan antara regulasi kemoresistensi dengan ekspresi MICA/B maupun dengan senesens pada GBM masih belum dipahami secara jelas. Untuk itu, pada penelitian ini dilakukan analisis ekspresi dan sekresi MICA/B juga analisis ekspresi marka senesens p16/p21 menggunakan RT-qPCR, flow cytometry, dan ELISA pada sel GBM yang sensitif maupun yang resisten terhadap TMZ. Hasil penelitian ini memperlihatkan bahwa pada sel GBM yang resisten terhadap TMZ terjadi penurunan ekspresi permukaan MICA/B dan peningkatan sekresi MICB, jika dibandingkan dengan sel GBM yang sensitif TMZ. Kemudian, hasil analisis tingkat senesens menunjukkan bahwa pada sel GBM yang resisten TMZ memiliki ekspresi p16/p21 yang lebih tinggi dari sel yang sensitif TMZ. Berdasarkan hasil-hasil tersebut dapat diketahui bahwa pembentukan kemoresistensi TMZ pada GBM terasosiasi dengan induksi senesens dan dapat berpengaruh terhadap regulasi MICA/B sehingga dapat menghambat sistem pengawasan imun GBM.

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Glioblastoma multiforme (GBM) is an aggressive and malignant cancer, having the highest incidence rate among primary malignant tumors of the central nervous system. Standard GBM treatment, including temozolomide (TMZ) chemotherapy, remains suboptimal due to potential GBM resistance to therapy. Prior studies have indicated that senescence influences the development of chemoresistance and the regulation of immunosurveillance by anticancer NK cells and cytotoxic T cells, particularly through MICA/B. However, the relationship between chemoresistance regulation, MICA/B expression, and senescence in GBM is not well understood. This study, therefore, examined MICA/B expression and secretion, along with the expression of the senescence markers p16/p21, in TMZ-sensitive and TMZ-resistant GBM cells using RT-qPCR, flow cytometry, and ELISA. The findings revealed that TMZ-resistant GBM cells exhibited reduced MICA/B surface expression and increased MICB secretion compared to TMZ-sensitive cells. Furthermore, the analysis of senescence levels showed that TMZ-resistant GBM cells had higher p16/p21 expression than TMZ-sensitive cells. These results suggest that the development of TMZ chemoresistance in GBM is linked to the induction of senescence and can impact MICA/B regulation, thereby hindering the immune surveillance system of GBM."