Table 5 Alternate paths taken up post perturbation

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].