Limits...
CREB3 subfamily transcription factors are not created equal: Recent insights from global analyses and animal models.

Chan CP, Kok KH, Jin DY - Cell Biosci (2011)

Bottom Line: Particularly, they were all thought to be proteolytically activated in response to endoplasmic reticulum (ER) stress to stimulate genes that are involved in unfolded protein response (UPR).Members of the CREB3 subfamily show differential activity despite their structural similarity.The spectrum of their biological function expands beyond ER stress and UPR.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry and State Key Laboratory for Liver Research, LKS Faculty of Medicine, The University of Hong Kong. dyjin@hkucc.hku.hk.

ABSTRACT
The CREB3 subfamily of membrane-bound bZIP transcription factors has five members in mammals known as CREB3 and CREB3L1-L4. One current model suggests that CREB3 subfamily transcription factors are similar to ATF6 in regulated intramembrane proteolysis and transcriptional activation. Particularly, they were all thought to be proteolytically activated in response to endoplasmic reticulum (ER) stress to stimulate genes that are involved in unfolded protein response (UPR). Although the physiological inducers of their proteolytic activation remain to be identified, recent findings from microarray analyses, RNAi screens and gene knockouts not only demonstrated their critical roles in regulating development, metabolism, secretion, survival and tumorigenesis, but also revealed cell type-specific patterns in the activation of their target genes. Members of the CREB3 subfamily show differential activity despite their structural similarity. The spectrum of their biological function expands beyond ER stress and UPR. Further analyses are required to elucidate the mechanism of their proteolytic activation and the molecular basis of their target recognition.

No MeSH data available.


Related in: MedlinePlus

Activation of membrane-bound transcription factors of the CREB3 subfamily. CREB3 subfamily proteins are anchored to the ER membrane in an inactive form when they are not stimulated. Only upon stimulation, the CREB3 subfamily proteins are translocated by COPII vesicles from the ER to the Golgi apparatus where they will encounter S1P and S2P proteases. They are cleaved to release the N-terminal fragments which will enter the nucleus to activate transcription of target genes. CREB3 subfamily proteins might work as homodimers or heterodimers in the nucleus to activate gene expression.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3116243&req=5

Figure 2: Activation of membrane-bound transcription factors of the CREB3 subfamily. CREB3 subfamily proteins are anchored to the ER membrane in an inactive form when they are not stimulated. Only upon stimulation, the CREB3 subfamily proteins are translocated by COPII vesicles from the ER to the Golgi apparatus where they will encounter S1P and S2P proteases. They are cleaved to release the N-terminal fragments which will enter the nucleus to activate transcription of target genes. CREB3 subfamily proteins might work as homodimers or heterodimers in the nucleus to activate gene expression.

Mentions: The CREB3 subfamily of bZIP transcription factors in mammals comprises CREB3 (also known as LZIP or Luman), CREB3L1 (OASIS), CREB3L2 (BBF2H7), CREB3L3 (CREB-H) and CREB3L4 (AIbZIP) [1]. CREB3, the prototype of this subfamily, was first identified through its interaction with a transcriptional coactivator termed host cell factor 1 (HCF1) [2]. CREB3L1 was initially found in long-term cultured mouse astrocytes and thought to have a role in gliotic events [3]. CREB3L2 was identified as part of a fusion oncoprotein named FUS-CREB3L2, which was generated by a chromosomal translocation in low grade fibromyxoid sarcoma (LGFMS) [4]. For CREB3L3, it was first reported to be a liver-specific transcription factor [5]. CREB3L4 was originally identified as a highly expressed and androgen-induced protein in prostate cancer cells [6]. The CREB3 subfamily members are closely-related to Drosophila dCREB-A/BBF2 [7,8]. They share significant homology within their bZIP domain that mediates DNA-binding and dimerization [9]. Similar to ATF6, they also feature a transmembrane domain at the immediate C-terminal side of the bZIP region (Figure 1) [1,10]. As such, they are type II membrane-associated proteins with the N-terminus facing the cytoplasm and the C-terminus penetrating through the endoplasmic reticulum (ER) membrane into the ER lumen [11,12]. Based on their structural similarity to ATF6, transcription factors of the CREB3 subfamily are thought to be activated through regulated intramembrane proteolysis (RIP) in response to ER stress [12]. Upon activation, they are transported from the ER to the Golgi apparatus and proteolytically cleaved there by site 1 protease (S1P) and S2P sequentially to release the N-terminal fragment, which translocates into the nucleus to activate the transcription of genes that play important roles in unfolded protein response (UPR) [12,13]. This model is generally applicable to ATF6 and all CREB3 subfamily transcription factors (Figure 2). In this model, the ER-anchored uncleaved full-length form of the transcription factor remains inactive. Activation through RIP ensures a rapid and timely response to ER stress and UPR [1,10,14-16]. RIP is therefore a rate-limiting step in transcription factor activation. In addition to RIP, there are several other regulatory points. For example, the N-terminal active form of CREB3 subfamily transcription factors can form homo- and hetero-dimers with differential transcriptional activity [9]. Particularly, CREB3L3 was suggested to form a heterodimer with ATF6 to synergistically activate target genes [17]. Whether this heterodimer is thermodynamically stable and functional remains to be determined.


CREB3 subfamily transcription factors are not created equal: Recent insights from global analyses and animal models.

Chan CP, Kok KH, Jin DY - Cell Biosci (2011)

Activation of membrane-bound transcription factors of the CREB3 subfamily. CREB3 subfamily proteins are anchored to the ER membrane in an inactive form when they are not stimulated. Only upon stimulation, the CREB3 subfamily proteins are translocated by COPII vesicles from the ER to the Golgi apparatus where they will encounter S1P and S2P proteases. They are cleaved to release the N-terminal fragments which will enter the nucleus to activate transcription of target genes. CREB3 subfamily proteins might work as homodimers or heterodimers in the nucleus to activate gene expression.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3116243&req=5

Figure 2: Activation of membrane-bound transcription factors of the CREB3 subfamily. CREB3 subfamily proteins are anchored to the ER membrane in an inactive form when they are not stimulated. Only upon stimulation, the CREB3 subfamily proteins are translocated by COPII vesicles from the ER to the Golgi apparatus where they will encounter S1P and S2P proteases. They are cleaved to release the N-terminal fragments which will enter the nucleus to activate transcription of target genes. CREB3 subfamily proteins might work as homodimers or heterodimers in the nucleus to activate gene expression.
Mentions: The CREB3 subfamily of bZIP transcription factors in mammals comprises CREB3 (also known as LZIP or Luman), CREB3L1 (OASIS), CREB3L2 (BBF2H7), CREB3L3 (CREB-H) and CREB3L4 (AIbZIP) [1]. CREB3, the prototype of this subfamily, was first identified through its interaction with a transcriptional coactivator termed host cell factor 1 (HCF1) [2]. CREB3L1 was initially found in long-term cultured mouse astrocytes and thought to have a role in gliotic events [3]. CREB3L2 was identified as part of a fusion oncoprotein named FUS-CREB3L2, which was generated by a chromosomal translocation in low grade fibromyxoid sarcoma (LGFMS) [4]. For CREB3L3, it was first reported to be a liver-specific transcription factor [5]. CREB3L4 was originally identified as a highly expressed and androgen-induced protein in prostate cancer cells [6]. The CREB3 subfamily members are closely-related to Drosophila dCREB-A/BBF2 [7,8]. They share significant homology within their bZIP domain that mediates DNA-binding and dimerization [9]. Similar to ATF6, they also feature a transmembrane domain at the immediate C-terminal side of the bZIP region (Figure 1) [1,10]. As such, they are type II membrane-associated proteins with the N-terminus facing the cytoplasm and the C-terminus penetrating through the endoplasmic reticulum (ER) membrane into the ER lumen [11,12]. Based on their structural similarity to ATF6, transcription factors of the CREB3 subfamily are thought to be activated through regulated intramembrane proteolysis (RIP) in response to ER stress [12]. Upon activation, they are transported from the ER to the Golgi apparatus and proteolytically cleaved there by site 1 protease (S1P) and S2P sequentially to release the N-terminal fragment, which translocates into the nucleus to activate the transcription of genes that play important roles in unfolded protein response (UPR) [12,13]. This model is generally applicable to ATF6 and all CREB3 subfamily transcription factors (Figure 2). In this model, the ER-anchored uncleaved full-length form of the transcription factor remains inactive. Activation through RIP ensures a rapid and timely response to ER stress and UPR [1,10,14-16]. RIP is therefore a rate-limiting step in transcription factor activation. In addition to RIP, there are several other regulatory points. For example, the N-terminal active form of CREB3 subfamily transcription factors can form homo- and hetero-dimers with differential transcriptional activity [9]. Particularly, CREB3L3 was suggested to form a heterodimer with ATF6 to synergistically activate target genes [17]. Whether this heterodimer is thermodynamically stable and functional remains to be determined.

Bottom Line: Particularly, they were all thought to be proteolytically activated in response to endoplasmic reticulum (ER) stress to stimulate genes that are involved in unfolded protein response (UPR).Members of the CREB3 subfamily show differential activity despite their structural similarity.The spectrum of their biological function expands beyond ER stress and UPR.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry and State Key Laboratory for Liver Research, LKS Faculty of Medicine, The University of Hong Kong. dyjin@hkucc.hku.hk.

ABSTRACT
The CREB3 subfamily of membrane-bound bZIP transcription factors has five members in mammals known as CREB3 and CREB3L1-L4. One current model suggests that CREB3 subfamily transcription factors are similar to ATF6 in regulated intramembrane proteolysis and transcriptional activation. Particularly, they were all thought to be proteolytically activated in response to endoplasmic reticulum (ER) stress to stimulate genes that are involved in unfolded protein response (UPR). Although the physiological inducers of their proteolytic activation remain to be identified, recent findings from microarray analyses, RNAi screens and gene knockouts not only demonstrated their critical roles in regulating development, metabolism, secretion, survival and tumorigenesis, but also revealed cell type-specific patterns in the activation of their target genes. Members of the CREB3 subfamily show differential activity despite their structural similarity. The spectrum of their biological function expands beyond ER stress and UPR. Further analyses are required to elucidate the mechanism of their proteolytic activation and the molecular basis of their target recognition.

No MeSH data available.


Related in: MedlinePlus