Chaudhary K, Deb S, Moniaux N, Ponnusamy M P, Batra S K
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA.
Oncogene. 2007 Nov 29;26(54):7499-507. doi: 10.1038/sj.onc.1210582. Epub 2007 Jun 18.
Genetic instabilities are believed to be one of the major causes of developing a cancer phenotype in humans. During the progression of cancer, aberrant expression of proteins, either owing to genetic (amplification, mutation and deletion) or epigenetic modifications (DNA methylation and histone deacetylation), contributes in different ways to the development of cancer. By differential screening analysis, an amplification of the 19q13 locus containing a novel pancreatic differentiation 2 (PD2) gene was identified. PD2 is the human homolog of the yeast RNA polymerase II-associated factor 1 (yPaf1) and is part of the human RNA polymerase II-associated factor (hPAF) complex. hPAF is comprised of five subunits that include PD2/hPaf1, parafibromin, hLeo1, hCtr9 and hSki8. This multifaceted complex was first identified in yeast (yPAF) and subsequently in Drosophila and human. Recent advances in the study on PAF have revealed various functions of the complex in human, which are similar to yPAF, including efficient transcription elongation, mRNA quality control and cell-cycle regulation. Although the precise function of this complex in cancer is not clearly known, some of its subunits have been linked to a malignant phenotype. Its core subunit, PD2/hPaf1, is amplified and overexpressed in many cancers. Further, an overexpression of PD2/hPaf1 results in the induction of a transformed phenotype, suggesting its possible involvement in tumorigenesis. The parafibromin subunit of the hPAF complex is a product of the HRPT-2 (hereditary hyperparathyroidism type 2) tumor suppressor gene, which is mutated in the germ line of hyperparathyroidism-jaw tumor patients. This review focuses on the functions of the PAF complex and its individual subunits, the interaction of the subunits with each other and/or with other molecules, and dysregulation of the complex, providing an insight into its potential involvement in the development of cancer.
遗传不稳定性被认为是人类发生癌症表型的主要原因之一。在癌症进展过程中，由于遗传（扩增、突变和缺失）或表观遗传修饰（DNA甲基化和组蛋白去乙酰化）导致的蛋白质异常表达，以不同方式促成了癌症的发展。通过差异筛选分析，发现19q13位点扩增，该位点包含一个新的胰腺分化2（PD2）基因。PD2是酵母RNA聚合酶II相关因子1（yPaf1）的人类同源物，是人类RNA聚合酶II相关因子（hPAF）复合体的一部分。hPAF由五个亚基组成，包括PD2/hPaf1、副纤维蛋白、hLeo1、hCtr9和hSki8。这种多面复合体首先在酵母（yPAF）中被鉴定出来，随后在果蝇和人类中也被发现。PAF研究的最新进展揭示了该复合体在人类中的各种功能，这些功能与yPAF相似，包括有效的转录延伸、mRNA质量控制和细胞周期调控。虽然该复合体在癌症中的精确功能尚不清楚，但其一些亚基已与恶性表型相关联。其核心亚基PD2/hPaf1在许多癌症中扩增并过度表达。此外，PD2/hPaf1的过度表达导致转化表型的诱导，表明其可能参与肿瘤发生。hPAF复合体的副纤维蛋白亚基是HRPT-2（2型遗传性甲状旁腺功能亢进）肿瘤抑制基因的产物，该基因在甲状旁腺功能亢进-颌骨肿瘤患者的种系中发生突变。本综述重点关注PAF复合体及其各个亚基的功能、亚基之间和/或与其他分子的相互作用以及复合体的失调，以深入了解其在癌症发展中的潜在作用。
