Nadir KOÇAK, İbrahim Halil YILDIRIM, Seval Cing YILDIRIM

Cellular functions of p53 and p53 gene family members p63 and p73

p53, hücre akıbetinin belirlenmesinde önemli rol oynayan hücre döngüsünün durdurulması veya programlı hücre ölümüne yönlendirilmesi gibi hücresel birçok yolağın düzenlenmesinde görev alan bir transkripsiyon faktörüdür. p53 aracılığı ile programlı hücre ölümünün başlatılması veya hücre çoğalmasının durdurulması, hasarlı DNA replikasyonunu ve genetik olarak normal olmayan hücrelerin çoğalmasını engellemektedir. Bu nedenle p53 işlevlerinin mutasyon ya da delesyon ile engellenmesi hücre homeostasisin sağlanmasında da ayrıca önemlidir. Bununla birlikte, çalışmalar p53\'ten yoksun farelerin ve Saos-2 gibi hücrelerin yaşamlarını devam ettirebildiklerini göstermektedir. Bu durum, p53\'ten yoksun olan organizmalarda p53 işlevini karşılayan p53-ilişkili proteinlerin olabileceğini düşündürmüştür. p53 ilişkili p63 ve p73 proteinlerinin keşfi, p53\'ten yoksun hücrelerde p53 bağımlı genlerin transkripsiyonlarına bir açıklama getirmiştir. p63 ve p73 proteinlerinin her ikisi de p53 proteini ile yüksek oranda benzerlik göstermekte ve p53\'ün bazı işlevlerini de paylaşmaktadırlar. p53\'ten farklı olarak p63 ve p73 insan kanserlerinde nadir olarak mutasyona uğramıştır. Burada p53 hakkındaki güncel bilgilerle beraber p53-ilişkili proteinler olan p63 ve p73 hakkındaki bilgileri de özetlemeye çalıştık.

Anahtar Kelimeler:

p53, p63, p73, hücre döngüsü, gen ailesi

Cellular functions of p53 and p53 gene family members p63 and p73

p53 is a transcription factor that regulates multiple cellular processes that are also important in cellular fates such as cell cycle arrest or programmed cell death. Induction of growth arrest or cell death by p53 prevents the replication of damaged DNA and proliferation of genetically abnormal cells. Therefore, inactivation of p53 by mutation or deletion is also important in ensuring the cellular homeostasis. However, studies showed that p53 deficient mice and cells such as Saos-2 cells are maintaining their life. This situation suggests that p53-related proteins might compensate the functions of p53 in p53 deficient organisms. The identification of two p53-related proteins, p63 and p73 revealed the transcription of p53 responsive genes in p53 deficient organisms. Both p63 and p73 proteins have high homology with the p53 protein and share some of the functions of p53. In contrast to p53, p63 and p73 rarely mutated in human cancers. Here we studied to summarize the current information about the p53 and other p53-related proteins, p63 and p73 that are included into the p53 gene family.

Keywords:

p53, p63, p73, cell cycle, gene family,

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Lane DP, Crawford LV. T antigen is bound to a host protein in SV40 transformed cells, Nature 1979; 278(2): 261-263.
Varley JM, Evans DGR, Birch JM. Li-Fraumeni syndrome-a molecular and clinical review, Brit J Cancer 1997; 76(1):1- 14.
Velculescu VE, El-Deiry WS. Biological and clinical impor- tance of the p53 tumor suppressor gene. Clin Chem 1996; 42 (6): 858-68.
Prives C, Manfredi JJ. The p53 tumor suppressor protein: meeting review. Genes Dev 1993; 7(4): 529-34.
Haris CC. Structure and function of the p53 tumor suppressor gene: clues for rational cancer therapeutic strategies. J Nat Can Inst 1996; 88(20): 1442-55.
Lin YL, Sengupta S, Gurdziel K, Bell GW, Jacks T, Flores ER. p63 and p73 transcriptionally regulate genes involved in DNA repair. PLos Genet 2009; 5(10):e1000680.
Lee HP. Tumor suppressor genes: a new era for molecular ge- netic studies of cancer. Breast Cancer Res Treatment 1991; 19(1): 3-13.
Mills AA, Zheng BH, Wang XJ, Vogel H, Roop DR, Bradley A. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 1999; 398(4):708-13.
Moll UM, Slade N. p63 and p73: Roles in development and tumor formation, Mol Cancer Res 2004; 2(7): 371-86.
Kaelin WG. The p53 gene family. Oncogene 1999; 18(11):7701-5.
http://www.ncbi.nlm.nih.gov/protein/11066970?from=1&t o=393&report=gpwithparts (09.02.2011).
Gabriel JA. The Biology of Cancer, (Second Ed.), John Wi- ley and Sons Ltd, West Sussex, England, 2007:37-40.
Bunz F. Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 1998; 282:1497-501.
Schulz WA. Molecular biology human cancers an advanced student’s textbook, Springer, Dordrecht, Netherlands 2007: 101-109.
Tan Y, Luo R. Structural and functional implications of p53 missens cancer mutations. PMC Biophysics 2009; 2(5): 1-10.
Meek DW. Tumour suppression by p53: a role for the DNA damage response? Nature 2009; 9(4):714-23.
Gasco M, Shami S, Crook T. The p53 pathway in breast cancer. Breast Cancer Res 2002; 4(1):70-6.
Ho CW, Fitzgerald MX, Marmorstein R. Structure of the p53 core domain dimer bound to DNA. J Biological Chem 2006; 281(42): 20494-502.
Devlin TM, Text Book of Biochemistry with clinical corre- lations, 6th ed., Wiley-Liss., Hoboken, NJ, USA 2006:185.
Yamaguchi Y. Watanabe H, Yirdiran S, et al. Detection of mutations of p53 tumor suppressor gene in pancreatic juice and its application to diagnosis of patients with pancreatic cancer: comparison with K-ras mutation. Clin Cancer Res 1999; 5: 1147-53.
Yang AN, Kaghad M, Wang YM, et al. p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant- negative activities. Mol Cell 1998; 2(2): 305-16. 22.
http://www.biotechniques.org/students/2006/Han/paper (18.01.2011).
Westfall MD, Pietenpol JA. p63: molecular complexity in development and cancer. Carcinogenesis 2004; 25 (6):857- 64.
Levrero M, Laurenzi VD, Costanzo A, Sabatini S, Gong J, Wang JYJ, Melino G. The p53/p63/p73 family of transcrip- tion factors: overlaping and distinct functions. J Cell Sci 2000; 113:1661-70.
Yang A, Schweitzer R, Sun DQ, et al. p63 is essential for re- generative proliferation in limb, craniofacial and epithelial development. Nature 1999; 398:714-8.
Kaghad M, Bonnet H, Yang A, et al. Monoallelically ex- pressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell 1997; 90(4): 809-19.
Melino G, Bernassola F, Ranalli M, et al. p73 induces apop- tosis via PUMA transactivation and bax mithocondrail translocation. J Biol Chem 2004; 279 (9):8076-83.