Ap1

AP-1 is one of the first gene-regulating transcription factors identified in mammalian cells. The key component of AP-1 complex is the Jun protein, which was originally identified as an oncoprotein encoded by a cellular insert in the genome of avian sarcoma virus 17.62 Jun can form a homodimer or heterodimer with Fos or ATF members. The most common AP-1 dimer is the Jun/Fos complex that recognizes the palindromic DNA sequence TGAC/GTCA, the so-called TPA response element (TRE), in the promoter or intron region of a number of genes.63 In addition, Jun can also form a complex with some activating transcription factor (ATF) members, such as ATF2, ATF3, and ATF4.63 All Jun proteins from different species contain an N-terminal JNK docking domain (delta domain) adjacent to the JNK phosphorylating site Ser63/73. In the C-terminal, there is a basic domain for DNA binding, followed by a nuclear localization signal (NLS) and a leucine zipper motif for dimerization with partner proteins.

Emerging evidence indicates that AP-1 plays an important role in oncogenesis. A number of studies suggest that active Ras-induced oncogenic transformation requires constitutive activation of AP-1.64'65 In immortalized rodent fibroblasts, experimental overexpression of c-jun is sufficient to induce oncogenic transformation in the absence of Ras. The transformational activity of AP-1 is mainly attributed to its anti-apoptotic effect, as evidenced by the fact that c-Jun protects cells against UV-induced cell death.6667 AP-1 appears to be able to suppress the expression of pro-apoptotic factor, Fas.67 Gene knockout and biochemical studies have suggested that the anti-apoptotic activity of an AP-1 component, especially the c-Jun subunit, is achieved by down-regulating the transcription of p53, a critical pro-apoptotic transcription factor.68 Further-more, ChIP experiments revealed a clear negative effect of c-Jun on association of p53 with the p21 promoter, resulting in a decreased expression of p21 and an increased G1 to S phase progression.69

It should be noted that a considerable number of reports indicated a pro-apoptotic effect of AP-1.70 The pro- or anti-apoptosis of AP-1 may be highly dependent on tissue type, development stages, and extracellular stimuli that determine which simultaneous and asynchronous signaling pathways are activated. For example, in the cells where p53 is deficient, AP-1 may exert anti-apoptotic effect. In contrast, in the cells where p53 is functionally normal, activation of AP-1 may be pro-apoptotic. As a transcription factor, the activity of AP-1 is reflected by its transcriptional regulation of target genes. Several anti-apoptotic and transformational genes have been recently identified, such as Jun-activated gene in CEF (JAC)71 and heparin-binding epidermal growth-factor-like growth factor (HB-EGF).72

Health And Fitness 101

Health And Fitness 101

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