PT  - JOURNAL ARTICLE
AU  - Lisa Maria Koch
AU  - Eivind Birkeland
AU  - Stefania Battaglioni
AU  - Xiao Helle
AU  - Mayura Meerang
AU  - Stefanie Hiltbrunner
AU  - Alfredo J. Ibáñez
AU  - Matthias Peter
AU  - Alessandra Curioni
AU  - Isabelle Opitz
AU  - Reinhard Dechant
TI  - Coincidence detection of mitogenic signals via cytosolic pH regulates Cyclin D1 expression
AID  - 10.1101/2020.07.15.202333
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.07.15.202333
4099  - http://biorxiv.org/content/early/2020/07/16/2020.07.15.202333.short
4100  - http://biorxiv.org/content/early/2020/07/16/2020.07.15.202333.full
AB  - Enhanced cell growth and proliferation are accompanied by profound changes in cellular metabolism. Originally identified as the Warburg effect in cancer, such metabolic changes are also common under physiological conditions and include increased fermentation and elevated cytosolic pH (pHc)1,2. However, how these changes contribute to enhanced cell growth and proliferation is unclear. Here, we demonstrate that elevated pHc specifically orchestrates an E2F-dependent transcriptional program to drive cell proliferation by promoting Cyclin D1 expression. pHc-dependent transcription of Cyclin D1 requires the transcription factors CREB1/ATF1 and ETS1 and the Histone Acetyltransferases p300/CBP. Interestingly, biochemical characterization revealed that the CREB1-p300/CBP interaction acts as a pH-sensor and coincidence detector linking different mitotic signals to Cyclin D1 transcription. We also show that elevated pHc contributes to increased Cyclin D1 expression in Malignant Pleural Mesotheliomas (MPMs) and renders them hypersensitive to pharmacological reduction of pHc. Taken together, these data demonstrate that elevated pHc is a critical cellular signal regulating G1 progression and provide a mechanism linking elevated pHc to oncogenic activation of Cyclin D1 in MPMs and possibly other Cyclin D1-dependent tumors. Thus, an increase of pHc may represent a functionally important, early event in the etiology of cancer amenable to therapeutic intervention.Competing Interest StatementThe authors have declared no competing interest.