A molecular mechanism for stress-induced alterations in susceptibility to disease.
Corticotropin-releasing hormone (CRH) is a 41-amino acid peptide which mediates behavioural and physiological responses to stress. A major target of CRH is the proopiomelanocortin (POMC) gene. Three transcription factors have been identified that affect transcription of the POMC gene by binding to two different sites within the CRH-responsive element of that promoter. We searched Genbank and found that nucleotide sequences in the POMC promoter which bind POMC-transcription factors are also contained in the genome of HIV-1 and cytomegalovirus, in c-fes and human MAT-1 breast cancer oncogenes, and in proinflammatory molecules, such as the interleukin-1 beta converting enzyme. We hypothesise a mechanism of hormone action by which a peptide hormone, such as CRH, might affect disease susceptibility by eliciting the production of transcription factors which may bind to unexpected intracellular targets, such as viruses, oncogenes, or the genes encoding for inflammatory mediators. Infection, inflammation, and possibly neoplastic transformation would thus be facilitated. This hypothesis can be tested. If confirmed, CRH antagonists may prove useful in the treatment of disorders whose pathophysiology involves molecules that respond to CRH-regulated POMC transcription factors.
Licinio
J
J
Clinical Neuroendocrinology Branch, National Institute of Mental Health, NIH, Bethesda, MD 20892-1284, USA.
Gold
P W
PW
Wong
M L
ML
D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics; D003346:Corticotropin-Releasing Hormone / Q000235:genetics* / Q000378:metabolism; D003587:Cytomegalovirus / Q000235:genetics; D020022:Genetic Predisposition to Disease; D016679:Genome, Viral; D015497:HIV-1 / Q000235:genetics; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008969:Molecular Sequence Data; D009857:Oncogenes / Q000235:genetics; D011333:Pro-Opiomelanocortin / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011519:Proto-Oncogenes / Q000235:genetics; D012689:Sequence Homology, Nucleic Acid; D013312:Stress, Physiological / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics
D018836:Inflammation Mediators; D014157:Transcription Factors; D011333:Pro-Opiomelanocortin; D003346:Corticotropin-Releasing Hormone; D011505:Protein-Tyrosine Kinases