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Table 5 Alternate paths taken up post perturbation

From: A molecular systems approach to modelling human skin pigmentation: identifying underlying pathways and critical components

Biological process perturbed gene UV induced melanin synthesis PTGER3_melan
Control Path UV- > Singlet_oxygen_kerat- > Ceramide_kerat- > PLA2_kerat- > Arachidonic_Acid_kerat- > PGE2_kerat- > PTGER3_melan- > PLC_melan- > DAG_melan- > PRKCB_melan- > TYR_melan- > Melanogensis
Alternate Path UV- > Singlet_oxygen_kerat- > Ceramide_kerat- > PRKCZ_kerat- > NFKB1_kerat- > EDN1_kerat- > EDNRB_melan- > PLC_melan- > DAG_melan- > PRKCB_melan- > TYR_melan- > Eumelanin_melan
Validation Addition of EDN1 induced increase in tyrosinase activity in cultured human melanocytes [59].
Biological Process Perturbed gene UV induced melanin synthesis
Tyr_melan
Control Path UV- > Singlet_oxygen_kerat- > Ceramide_kerat- > PLA2_kerat- > Arachidonic_Acid_kerat- > PGE2_kerat- > PTGER3_melan- > PLC_melan- > DAG_melan- > PRKCB_melan- > TYR_melan- > Melanogensis
Alternate Path None
Validation Tyrosinase mutations lead to albinism or hypopigmentation (MGI)
Biological Process Perturbed gene UV induced dendrite formation
KIT_melan
Control Path UV- > Singlet_oxygen_kerat- > Ceramide_kerat- > PRKCZ_kerat- > NFKB1_kerat- > KITLG_kerat- > KIT_melan- > PIK3CA_melan- > RAC1_melan- > RAC1:PARD6A:CDC42_melan- > PRKCZ_melan- > Dendrite_formation_melan
Alternate Path UVB- > Lipid_Peroxidation_kerat- > 4HNE_kerat- > DNA_Damage_kerat- > TP53_kerat- > ACTH_kerat- > MC1R_melan- > ADCY4_melan- > cAMP_melan- > RAP1A_melan- > RAC1_melan- > RAC1:PARD6A:CDC42_melan- > PRKCZ_melan- > Dendrite_formation_melan
Validation Highly dendritic melanocytes are stimulated by injection of alpha-MSH in newborn mice. Formation and translocation of melanosomes to dendrites is triggered by alpha-MSH [60].
Biological Process Perturbed gene UV induced melanosme phagocytosis
F2RL1_kerat
Control Path UV- > Singlet_oxygen_kerat- > Ceramide_kerat- > PRKCZ_kerat- > NFKB1_kerat- > F2RL1_kerat- > RHOA_kerat- > Melanosome_phagocytosis_kerat
Alternate Path None
Validation RWJ-50353, a serine protease inhibitor, led to reduced pigment deposition in melanocytes and de-pigmentation. Immature melanosomes accumulate inside melanocytes and there is abnormal dendrite dynamics in RWJ-50353-treated epidermal equivalents [61].
Biological Process Perturbed gene UV induced melanocyte proliferation
NFKB1_kerat
Control Path UV- > Singlet_oxygen_kerat - > Ceramide_kerat- > PRKCZ_kerat- > NFKB1_kerat- > CSF2_kerat- > CSF2RA_melan- > CSF2RA:JAK1_melan- > STAT3_melan- > CCND1_melan- > CDK4:CCND1_melan- > Cell_proliferation_melan
Alternate Path UVB- > Lipid_Peroxidation_kerat- > 4HNE_kerat- > DNA_Damage_kerat- > TP53_kerat- > ACTH_kerat- > MC1R_melan- > ADCY4_melan- > cAMP_melan- > PRKACA_melan- > CREB1_melan- > MITF_melan- > CDK4_melan- > CDK4:CCND1_melan- > Cell_proliferation_melan
Validation In T-oligos pre-treated and UV light-irradiated keratinocytes, NFκB binding to the transcriptional co-activator p300 decreased relative to control whereas the amount of p53 binding to p300 was strikingly increased demonstrating activation of p53 and repression of NFkB upon DNA damage in keratinocytes which could serve as an alternate path when NFkB is perturbed [62].
  1. Validation refers to observations from literature that could possibly support the existence of such pathways.